Method and device to restore and/or improve nervous system functions by modifying specific nervous system pathways

ABSTRACT

The present invention provides methods, devices, and systems for restoring or improving nervous system function of a subject. Provided is a method involving: (i) providing an operant conditioning protocol effective to produce targeted neural plasticity (TNP) in a primary targeted central nervous system (CNS) pathway of a subject; and (ii) administering the operant conditioning protocol to the subject to elicit TNP in the primary targeted CNS pathway and to elicit generalized neural plasticity (GNP) in one or more other CNS pathway. The elicitation of the GNP in the one or more other CNS pathway serves to restore or improve a nervous system function of the subject. Provided is a device comprising a nerve stimulation-electromyographic recording component and a controller for operating the nerve stimulation-electromyographic recording component in accordance with an operant conditioning protocol.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. Provisional PatentApplication Ser. No. 61/678,671, filed Aug. 2, 2012, the disclosure ofwhich is hereby incorporated by reference herein in its entirety.

GOVERNMENT RIGHTS STATEMENT

This invention was made with Government support under grant numbersNS069551, NS022189, NS061823, and HD036020 awarded by the NationalInstitutes of Health. The United States Government has certain rights inthe invention.

FIELD OF THE INVENTION

The present invention generally relates to the field of neurologicalrehabilitation. In certain embodiments, the present invention relates tomethods, devices, and systems for restoring and/or improving nervoussystem function of a subject.

BACKGROUND OF THE INVENTION

The primary goal of neurological rehabilitation is to restore importantmotor and cognitive skills that have been impaired by injury or disease.Current therapeutic methods consist primarily of the repeated practiceof these skills (e.g., treadmill locomotion, reach and grasp actions)(Wernig and Muller, 1992; Edgerton et al., 1997; Harkema et al., 1997;Taub et al., 1999; Wernig et al., 2000; Edgerton et al., 2001; Maegeleet al., 2002; Taub and Uswatte, 2003; Wolf et al., 2006; Edgerton etal., 2008), with the expectation that this practice will lead toplasticity that improves function (Koski et al., 2004; Thickbroom etal., 2004; Thomas and Gorassini, 2005; Yen et al., 2008). Although thisstrategy is logical and often beneficial, it is seldom completelysuccessful.

The skills that rehabilitation attempts to restore normally depend onplasticity throughout the central nervous system (CNS), from thecerebral cortex to the spinal cord (Drew et al., 2002; Nielsen, 2002;Hultborn and Nielsen, 2007; Wolpaw, 2010; Rossignol and Frigon, 2011).Moreover, the location and nature of the damage that impairs performancediffer widely from individual to individual, as well as from disorder todisorder. As a result, the plastic changes (i.e., persistent changes)needed to restore a particular skill (e.g., locomotion) are also likelyto differ widely across individuals. Thus, new therapeutic methods thatcan induce plasticity in particular CNS pathways, and can thereby targeteach individual's particular deficits, might significantly increase theeffectiveness of rehabilitation.

In both animals and humans, operant conditioning protocols can modifyspecific spinal reflex pathways (Wolpaw and O'Keefe, 1984; Wolpaw, 1987;Chen and Wolpaw, 1995; Wolf and Segal, 1996; Carp et al., 2006a; Chen etal., 2006a; Thompson et al., 2009). Because these spinal pathwaysparticipate in important skills such as locomotion, conditioningprotocols might be used to reduce the functional deficits produced byspinal cord injuries, strokes, and other disorders. An initial animalstudy supports this hypothesis. In rats in which a lateralized spinalcord injury (SCI) had produced a gait asymmetry, appropriateconditioning of the soleus H-reflex on the injured side eliminated theasymmetry and restored more normal locomotion (Chen et al., 2006b).

The spinal stretch reflex (SSR) (i.e., the tendon jerk) and itselectrical analog, the H-reflex are the simplest motor behaviors. Theyare produced primarily by a two-neuron, monosynaptic pathway comprisedof the primary afferent fiber, its synapse on the motoneuron, and themotoneuron itself (Wolpaw et al., 1983, Wolpaw, 1987). Because it isaffected by descending activity from the brain, this pathway can beoperantly conditioned. In response to a conditioning protocol, monkeys,humans, rats, and mice can gradually increase (i.e., up-conditioning) ordecrease (i.e., down-conditioning) the SSR or the H-reflex (Wolpaw 2010for review). The larger or smaller reflex that results is a simple motorskill (i.e., “an adaptive behavior acquired through practice” (Chen etal. 2005)). H-reflex conditioning is accompanied by neuronal andsynaptic plasticity at multiple sites in the spinal cord and brain(Wolpaw and Chen 2009 for review).

H-reflex conditioning is a powerful model for exploring the mechanismsand principles of skill acquisition and maintenance (Wolpaw 2010). Thespinal cord is the final common pathway for all motor behavior, andspinal cord plasticity has a part in the acquisition and maintenance ofmany motor skills. Furthermore, by virtue of their simplicity,accessibility, separation from the brain, and closeness to behavior, thespinal cord in general and the H-reflex in particular are uniquelysuited for studying how activity-dependent plasticity (particularlygradual plasticity) explains behavior, and for formulating concepts andidentifying principles that may apply to learning throughout the CNS.

Because the spinal cord is the final common pathway for motor output,the spinal cord plasticity associated with H-reflex conditioning affectsother behaviors. For example, in normal rats, right soleus muscleH-reflex up- and down-conditioning produce corresponding changes in theright soleus burst during locomotion (Chen et al. 2005). Nevertheless,despite this change, the right/left symmetry of the step cycle ispreserved. This suggests that changes in other reflex pathwayscompensate for the locomotor effects of the change in the soleusH-reflex pathway. This hypothesis is supported by other evidence thatthe functional effects of H-reflex conditioning extend beyond theconditioned reflex, and even to the contralateral side of the spinalcord (Wolpaw and Lee 1989).

To date, there is generally a lack of methods, devices, and systems thatcan be used by subjects and patients to restore and/or improve nervoussystem functions, particularly in a self-administered or outpatientmanner. Therefore, novel strategies that can complement current methodsand thereby enhance and/or restore important motor and cognitive skillsthat have been impaired by injury or disease are needed.

The present invention is directed to overcoming the current deficienciesin the art of neurological rehabilitation.

SUMMARY OF THE INVENTION

The present invention relates to methods, devices, and systems forrestoring and/or improving nervous system function of a subject. In ageneral sense, the present invention provides new and useful methods,devices, and systems for use in the field of neurologicalrehabilitation. In addition, the present invention provides new anduseful methods, devices, and systems for use by those who wish toimprove and/or reach their optimal performance potential with respect totheir central nervous system (CNS) sensorimotor and/or cognitivefunctions (e.g., athletic performance, memory skills, etc.).

In one aspect, the present invention provides a method for restoring orimproving nervous system function of a subject. This method involves thesteps of (i) providing an operant conditioning protocol effective toproduce targeted neural plasticity (TNP) in a primary targeted centralnervous system pathway of a subject; and (ii) administering the operantconditioning protocol to the subject under conditions effective toelicit TNP in the primary targeted CNS pathway and to elicit generalizedneural plasticity (GNP) in one or more other CNS pathway. Theelicitation of the GNP in the one or more other CNS pathway serves torestore or improve a nervous system function of the subject.

In another aspect, the present invention provides a device for restoringor improving nervous system function of a subject. The device comprisesa nerve stimulation-electromyographic recording component and acontroller for operating the nerve stimulation-electromyographicrecording component in accordance with an operant conditioning protocol.The a nerve stimulation-electromyographic recording component comprisesa nerve stimulator for stimulating a primary targeted central nervoussystem pathway in a subject, at least one stimulating electrode array infunctional communication with the nerve stimulator and adapted fortopical contact with the subject, and at least one electromyographic(EMG) recording electrode array for recording EMG data of the subjectproduced in response to the stimulation of the primary targeted CNSpathway. As mentioned, the device also comprises a controller foroperating the nerve stimulation-electromyographic recording component inaccordance with an operant conditioning protocol. The operantconditioning protocol is effective to produce targeted neural plasticity(TNP) in the primary targeted CNS pathway of the subject.

In certain embodiments, the device of the present invention furthercomprises a wearable placement component for positioning the at leastone stimulating electrode array at a stimulation target area of thesubject and/or for positioning the at least one EMG recording electrodearray at an EMG recording target area of the subject.

In certain other embodiments, the device of the present inventionfurther comprises a wireless communication device for receiving,displaying, storing, and/or analyzing data generated by the controller.

In one aspect, the present invention relates to a novel method forrestoring and/or improving central nervous system sensorimotor and/orcognitive functions.

The discovery of the method for improving important CNS functions byusing operant conditioning protocols to produce targeted neuralplasticity (TNP) in specific central nervous system (CNS) pathways wasfirst reported in by the present inventors in Thompson et al., 2013. Ina first embodiment, the method of the present invention used it toimprove walking in people in whom a chronic incomplete spinal cordinjury (SCI) had produced a spastic gait disorder characterized byhyperactive reflexes, abnormal reflex modulation in ankle extensormuscles, and/or weak ankle dorsiflexion leading to foot drop (Dietz andSinkjaer, 2007, Nielsen et al., 2007, Barthelemy et al., 2010). Becauseof these abnormalities, the subjects walked very slowly and with greatdifficulty, and usually needed an assistive device such as crutches or awalker. By down-conditioning the soleus H-reflex in the most impairedleg, the present invention greatly reduced these abnormalities andmarkedly improved the entire behavior of walking; muscles in both legsbehaved more normally and contributed more effectively to walking. Thesubjects walked faster and more symmetrically (i.e., they limped less),and the modulation of muscle activity across the step cycle increased inboth legs. Furthermore, they commented spontaneously that they werewalking faster and farther in their daily lives, and a number noted lessabnormal reflex activity, easier stepping, less dependence on anassistive device, and/or other improvements. These first results showedthat the methods provides a valuable new approach to restoring usefulfunction after spinal cord injuries and probably in other neuromusculardisorders as well. Example 2 provides a full description of oneembodiment of the first demonstration of the method.

This discovery that the method had extremely broad beneficial impact onan important motor skill (i.e., walking) was wholly unexpected and notpredictable from previously available knowledge. The discovery indicatesthat this novel method provides an entirely new approach to improvingstandard neuromuscular skills, such as walking, or special skills, suchas athletics, that are normally improved through repeated practice ofthe skills and/or parts of them. As noted herein, this new methodmodifies specific nervous system pathways through an operantconditioning protocol. These pathway-specific changes (i.e., targetedneural plasticity (TNP)) have widespread effects on the complex nervoussystem networks that produce neuromuscular skills, and they can therebyimprove these skills beyond the levels possible with conventionalpractice. The method can improve neurorehabilitation in people withdisabilities due to spinal cord injury, stroke, cerebral palsy, braininjury, or other disorders. It may also enable people withoutdisabilities to reach levels of skill performance beyond those possiblethrough conventional practice (e.g., athletes, dancers, etc.). In sum,the present invention can, inter alia, improve neuromuscular skills, andpotentially cognitive skills as well, to levels beyond those reachablethrough conventional practice. Further, to implement the method in aportable and/or subject-administered manner, provided herein are devicesand systems that are used to perform the method of the presentinvention.

These and other objects, features, and advantages of this invention willbecome apparent from the following detailed description of the variousaspects of the invention taken in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating aspects of the present invention, thereare depicted in the drawings certain embodiments of the invention.However, the invention is not limited to the precise arrangements andinstrumentalities of the embodiments depicted in the drawings. Further,as provided, like reference numerals contained in the drawings are meantto identify similar or identical elements.

FIG. 1 is an illustration of a standard laboratory set-up for operantconditioning of the soleus H-reflex.

FIG. 2 is an illustration one embodiment of a spinal reflex operantconditioning system as disclosed herein.

FIG. 3 is an illustration of one embodiment of a device as disclosedherein. In this embodiment, device 17 is in the form of a leg wrap andis shown in its open position to show the popliteal simulating electrodearray (“stimulation array”) and the soleus muscle recording electrodearray (“recording array”). A “ground” electrode is also illustrated.

FIG. 4 are illustrations of various views (i.e., face, side, top end,and bottom end views) of one embodiment of a nervestimulation-electromyographic (NS-EMG) device 18 that compriseselectronics that can be embedded in a pocket of a leg wrap embodiment ofdevice 17 shown in FIG. 3. As shown, in various embodiments, NS-EMGdevice 18 can be encased in a waterproof (IPX-7) plastic case.

FIG. 5 is an illustration of one embodiment of a system comprising adevice and implementing a method according to the present disclosure.This figure illustrates one embodiment of an initial set-up andsubsequent communication of a device of the present disclosure with acloud service and a user interface.

FIG. 6 is an illustration of one embodiment of a system comprising adevice and implementing a method according to the present disclosure.This figure illustrates one embodiment of aspects of a system includingstimulation and recording of the nerve stimulation and electromyographic(EMG) recording interfaces.

FIG. 7 are graphs showing effects of SOL_(R) HRup and HRdownconditioning. Average final conditioning H-reflex, background EMG, and Mwave (in % of their initial values) of SOL_(R), QD_(R), and SOL_(L) forthe successful HRup and HRdown rats. P values for difference frominitial value by paired t-test are shown. *: P<0.05; ***: P<0.001.

FIG. 8 are graphs showing effects of SOL_(R) HRup and HRdownconditioning on the conditioning H-reflexes of representative rats.Average post-stimulus SOL_(R) and QD_(R) EMG for a control day (solid)and a day near the end of conditioning (dashed) for an HRup rat and anHRdown rat. After HRup conditioning the SOL_(R) H-reflex is larger andthe QD_(R) H-reflex is smaller, while after HRdown conditioning theSOL_(R) H-reflex is smaller and the QD_(R) H-reflex is larger.Background EMG (EMG at time zero) and M-responses do not change. Peaksin the first 1-2 ms after stimulation are stimulus artifacts.

FIGS. 9A-9B are graphs showing effects of SOL_(R) HRup and HRdownconditioning on the locomotor H-reflexes. FIG. 9A: Average finallocomotor H-reflexes (in % of their initial values) of SOL_(R) andQD_(R) muscles for successful HRup (left) and HRdown (right) rats. Pvalues for difference from initial value by paired t-test are shown. *:P<0.05; **: P<0.01. FIG. 9B: Effects of SOL_(R) HRup and HRdownconditioning on the locomotor H-reflexes in representative rats. Averagepost-stimulus SOL_(R) and QD_(R) EMG in the stance phase of locomotionduring the control-mode (solid) and near the end of conditioning(dashed) for an HRup rat and an HRdown rat. After HRup conditioning, theSOL_(R) H-reflex is larger and the QD_(R) H-reflex is smaller, whileafter HRdown conditioning the SOL_(R) H-reflex is smaller and the QD_(R)H-reflex is larger. Pre-stimulus EMG (EMG at time zero) and M-responsesare stable. Peaks in the first 1-2 ms after stimulation are stimulusartifacts.

FIG. 10 are graphs showing Kinematic effects of SOL_(R) HRup and HRdownconditioning. Individual and average (±SEM) final right stance-phaseanterior ankle, posterior knee, and anterior hip angles (see inset), andhip height (in % of their initial values) for successful HRup (left) andHRdown (right) rats. The dashed horizontal line is parallel to thetreadmill surface. P values for difference from the initial value bypaired t-test are shown (*: P<0.05; **: P<0.01).

FIGS. 11A-11C are illustrations of various aspects of one embodiment ofthe present invention. FIG. 11A is a session schedule. Six Baselinesessions were followed by 30 Conditioning (DC subjects) or Control (UCsubjects) sessions, and then by two Follow-up sessions. FIG. 11B is aComposition of Baseline, Control, Conditioning, and Follow-up sessions.FIG. 11C shows visual feedback screens for Control and Conditioningtrials.

FIGS. 12A-12C are graphs showing H-reflexes from a successful DC subjectduring the Baseline period and at the end of the 30 Conditioningsessions. FIG. 12A: Final Conditioned H-reflex sizes (i.e., average forthe last 3 Conditioning sessions) for individual Conditioning (DC) andUnconditioned (UC) subjects. The data for normal DC subjects are fromThompson et al. (2009). The filled triangles represent the DC subjectswhose Conditioned H-reflexes for the last 6 Conditioning sessions weresignificantly less than their H-reflexes for the 6 Baseline sessions.The open triangles represent the DC subjects in whom the H-reflex didnot decrease significantly. (The lowest open triangle failed to reachstatistical significance due to high inter-session variability.) FIGS.12B and 12C: Average Conditioned (FIG. 12B) and Control (FIG. 12C)H-reflexes for a Baseline session (solid) and the last Conditioningsession (dashed) from a DC subject with SCI in whom the H-reflexdecreased significantly. Both Conditioned and Control H-reflexes aresmaller after 30 Conditioning sessions. As summarized in FIGS. 13A and13B, the decrease in the Control H-reflex is nearly as great as that inthe Conditioned H-reflex. Background EMG and M-wave do not change. Asmall stimulus artifact is present.

FIGS. 13A-13F: Average (±SE) H-reflex values for Baseline andConditioning sessions for DC subjects with SCI (FIGS. 13A-13C, N=6, thisstudy) and for normal subjects (FIGS. 13D-13F, N=8 (Thompson et al.,2009)) in whom the H-reflex decreased significantly. FIGS. 13A and 13D:Average Conditioned H-reflex size. FIGS. 13B and 13E: Average ControlH-reflex size. FIGS. 13C and 13F: Average of Conditioned H-reflex sizeminus Control H-reflex size (i.e., task-dependent adaptation (seeResults)). (see Thompson et al. (2009) for details). In the subjectswith SCI, the Conditioned H-reflex decreases to 69% of the baselinevalue over 30 Conditioning sessions (FIG. 13A). This decrease consistsof a relatively small task-dependent adaptation (−7%, FIG. 13C) and arelatively large across-session Control reflex decrease (−24%, FIG.13B). In the subjects without disability (Thompson et al., 2009), theConditioned H-reflex also decreases to 69% of the baseline value over 24Conditioning sessions (FIG. 13D). This decrease consists of a relativelylarge task-dependent adaptation (−15%, FIG. 13F) and a relatively smallacross-session Control reflex decrease (−16%, FIG. 13E). The asterisksbetween FIGS. 13B and 13E and between FIGS. 13C and 13F indicatesignificant differences (p<0.01) between subjects with SCI and normalsubjects in final Control H-reflex value and in task-dependentadaptation, respectively. Task-dependent adaptation is greater in thenormal subjects, while change in the Control H-reflex is greater in thesubjects with SCI.

FIGS. 14A-14C: FIG. 14A: Average (±SE) 10-m walking speeds after 30Conditioning or Control sessions (in % of Baseline speed) for subjectsin whom the H-reflex did or did not decrease significantly. FIG. 14B:Step-cycle symmetry before (open bars) and after (shaded bars) 30Conditioning or Control sessions for subjects in whom the H-reflex didor did not decrease significantly. Symmetry is measured as the ratio ofthe time between the nonconditioned leg's foot contact (nFC) and theconditioned (or simply stimulated, in the case of UC subjects) leg'sfoot contact (cFC) to the time between cFC and nFC. A ratio of 1indicates a symmetrical gait. Initially, the ratio is >1. After the 30Conditioning or Control sessions, the ratio has decreased toward 1 inthe subjects in whom the H-reflex decreased while it has increased inthe subjects in whom the H-reflex did not decrease. FIG. 14C: Successivestep cycles before and after conditioning from a subject in whom theH-reflex decreased. Each nFC (•) and cFC (∘) is shown. The shortvertical dashed lines mark the midpoints between nFCs (i.e., themidpoints of the step-cycle), which is when cFC should occur. BeforeH-reflex down-conditioning, cFC occurs too late; after successfuldown-conditioning, it occurs on time.

FIG. 15 are graphs showing locomotor EMG activity in soleus, tibialisanterior (TA), vastus lateralis (VL), and biceps femoris (BF) muscles ofboth legs before (solid) and after (dashed) conditioning in a DC subjectwith SCI in whom the soleus H-reflex decreased. The step cycle isdivided into 12 equal bins, starting from foot contact. Thus, bins 1-7are for the stance phase and bins 8-12 are for the swing phase. Aftersuccessful down-conditioning, EMG modulation over the step cycleincreases in both legs.

FIG. 16 are graphs showing rectified soleus EMG and locomotor H-reflexsize over the step cycle before and after H-reflex down-conditioning ina DC subject with SCI in whom the H-reflex decreased. The reducedspasticity after conditioning produces better soleus EMG modulation: theabnormal activity during the swing phase (arrows) is no longer present.In addition, the locomotor H-reflex is greatly decreased and bettermodulated after conditioning (i.e., it is lowest during the swingphase).

FIG. 17: Spontaneous comments made by subjects over the course of datacollection. “x” indicates when a subject made the comment for the firsttime. Note that every subject in whom the H-reflex decreased reportedwalking faster and farther, and that these reports did not occur untilsubstantial H-reflex decrease had occurred (i.e., FIGS. 13A-13F).

DETAILED DESCRIPTION OF THE INVENTION

In a general sense, the present invention provides new and usefulmethods, devices, and systems for use in the field of neurologicalrehabilitation. More particularly, the present invention providesmethods, devices, and systems for restoring and/or improving nervoussystem function of a subject, whether the subject is a patient in needof neurological rehabilitation or a person interested in improving ormaximizing his neurological function in a particular area. Therefore, incertain aspects, the present invention provides new and useful methods,devices, and systems for use by those who wish to improve and/or reachtheir optimal performance potential with respect to their centralnervous system (CNS) sensorimotor and/or cognitive functions (e.g.,athletic performance, memory skills, etc.).

As used herein, the term “subject” refers to an animal or human in needof neurological rehabilitation or desirous of improving, restoring,and/or both improving and restoring a nervous system function or aspectthereof. A subject can be of any age or gender. Further, a subject caninclude a patient of neurological rehabilitation, or a person havingnormal nervous system function.

As used herein, the term “nervous system function” refers to anyfunction related to the nervous system of a subject. The nervous systemfunction can be important or secondary. The nervous system function canbe, without limitation, any CNS sensorimotor function or cognitivefunction. Examples of nervous system functions can include, withoutlimitation, locomotion (walking), reach-and-grasp functions, withdrawalresponses, hand control, arm control, attention, perception, emotionalcontrol, reading, arithmetic, memory, and other cognitive or nervoussystem functions, including those not specifically named herein butunderstood by those of ordinary skill in the art to be cognitive ornervous system functions.

Method of Improving Nervous System Function

In one aspect, the present invention provides a method for restoring orimproving nervous system function of a subject. This method involves thesteps of (i) providing an operant conditioning protocol effective toproduce targeted neural plasticity (TNP) in a primary targeted centralnervous system (CNS) pathway of a subject; and (ii) administering theoperant conditioning protocol to the subject under conditions effectiveto elicit TNP in the primary targeted CNS pathway and to elicitgeneralized neural plasticity (GNP) in one or more other CNS pathway.The elicitation of the GNP in the one or more other CNS pathway servesto restore or improve a nervous system function of the subject.

In one embodiment, the method of the present invention can beimplemented by using a device or system of the present invention asdisclosed herein.

In one embodiment of this method, the operant conditioning protocol isself-administered by the subject.

Suitable operant conditioning protocols for use in the method of thepresent invention are as described herein. In various embodiments, theoperant conditioning protocol is designed to down-condition hyperactivereflexes in the subject, up-condition hypoactive reflexes in thesubject, and/or up-condition or down-condition other CNS pathways.

As provided herein, the method of the present invention provides operantconditioning protocols effective to produce targeted neural plasticity(TNP) in a primary targeted CNS pathway of a subject. Suitable primarytargeted CNS pathways of the subject can include, without limitation, amonosynaptic pathway of a spinal stretch reflex, a monosynaptic pathwayof a Hoffman reflex (H-reflex), a spinal pathway of cutaneous reflexes,a corticospinal tract, a reciprocal thalamocortical pathway thatproduces electroencephalographic (EEG) sensorimotor rhythms (SMRs), andother CNS pathways, including other CNS pathways not specifically namedherein but understood to be CNS pathways by those of ordinary skill inthe art.

As provided herein, in accordance with various embodiments of the methodof the present invention, operant conditioning protocols areadministered to a subject under conditions effective to elicit TNP inthe primary targeted CNS pathway and to elicit generalized neuralplasticity in one or more other CNS pathway. As used herein, the one ormore other CNS pathway can include, without limitation, other spinalreflex pathways, other corticospinal connections, intracerebralconnections, cortical-subcortical pathways, and any other CNS pathway,including other CNS pathways not specifically named herein butunderstood to be CNS pathways by those of ordinary skill in the art.

As set forth herein, the method is for restoring and/or improvingnervous system function in a subject. In various embodiments, therestored and/or improved nervous system function includes, withoutlimitation, locomotion (walking), a withdrawal response, hand control,arm control, reach-and-grasp control, attention, perception, emotionalcontrol, reading, arithmetic, memory, and other cognitive functions.

In further aspects, the present invention provides various otherembodiments of a method for restoring and/or improving nervous systemfunction in a subject. As provided in the examples contained herein, inaccordance with aspects of the present invention, an operantconditioning protocol produces targeted neural plasticity (TNP) in theCNS that leads to additional beneficial plasticity at many other CNSsites, and can thereby greatly improve all aspects of a complex behaviorthat has been impaired by trauma or disease. For example, in people inwhom an incomplete spinal cord injury has produced spasticity andfoot-drop in one leg that greatly impairs walking, operant conditioningthat weakens a particular overactive reflex pathway in that leg leads towidespread plasticity that improves all aspects of walking, includingmuscle activity in the opposite leg (Thompson et al., 2013). That is,the benefits of operant conditioning of a single reflex pathway go farbeyond the direct effects of the TNP in the targeted reflex pathwayitself: the entire behavior of walking becomes faster and moresymmetrical (e.g., limping disappears and muscles on both sides behavemore effectively). In sum, the TNP produced by an appropriate reflexoperant conditioning protocol focused on a correctly chosen single CNSpathway triggers widespread beneficial plasticity that improves walkingin general. This profound and widespread impact was not expected, muchless demonstrated, until the present invention. Thus, the presentinvention provides novel methods for rehabilitation, since the samemethod could be applied to other CNS pathways, and could improve a broadspectrum of important CNS functions.

Now that this effect has been discovered, it can be understood as aresult of the continual adaptive processes occurring in the CNS. Withoutintending to be limited by any particular theory, as behaviors (i.e.,CNS functions) are performed, the CNS is continually evaluating theresults and producing plasticity at one or more of the many CNS sitesinvolved in the behavior so as to optimize performance. By producingappropriate plasticity at one of these sites (i.e., targeted neuralplasticity (TNP)), a properly selected operant conditioning protocolchanges the ongoing interactive process of multisite adaptive plasticityand enables the CNS to arrive at a superior solution; that is, itenables the CNS to adjust many of the involved sites (i.e., to producegeneralized neural plasticity (GNP)) so as to improve the behavior to alevel superior to that obtained prior to exposure to the operantconditioning protocol.

In one embodiment of the method of the present invention, there isprovided a method with well-defined steps, as well as a particularexemplary embodiment of the method. The purpose of this method is toimprove the performance of complex nervous system functions. Asdiscussed herein, to do this, it uses operant conditioning protocols toproduce targeted neural plasticity (TNP) in specific central nervoussystem (CNS) pathways that have important roles in the functions. ThisTNP triggers further plasticity in other CNS pathways important to thefunctions and thereby leads to widespread improvement in the functions.This method can be applied to improve basic motor skills such as walkingor reach-and-grasp, as well as higher-level CNS functions (e.g.,attention, perception, emotional control, memory, reading, andarithmetic). Furthermore, it can be used for rehabilitation (i.e., torestore functions that have been impaired by injury or disease) or toenhance specific functions beyond their normal level in people withoutdisabilities.

In an embodiment of the present invention, the method exposes theindividual to an operant conditioning protocol in which the responsebeing conditioned is produced by a specific and well-defined CNS pathwaythat also contributes to much more complex and important CNS behaviorssuch as walking. The protocol produces TNP in the pathway; that is, itchanges the pathway, and as a result it also affects the complexbehaviors (e.g., walking) that use the pathway. Surprisingly, byaffecting another behavior such as walking, the TNP in the targetpathway also triggers widespread plasticity in other pathways thatcontribute to that other behavior. In an individual with functionimpaired by CNS trauma or disease, induction of this widespreadplasticity can improve an impaired behavior toward normal. In a healthyindividual without CNS trauma or disease, induction of TNP plasticity byan appropriately selected protocol may improve a behavior beyond itsnormal range.

Table 1 includes a listing of various examples of how the method of thepresent invention can be applied, as follows:

TABLE 1 Examples of Applications of the Method Behavioral context CNSpathway of the operant CNS output that targeted for conditioningdetermine CNS function plasticity protocol reward/no reward that isimproved Monosynaptic Steady-state muscle Spinal stretch Walking pathwayof the spinal activity (EMG) or a reflexes or H- stretch reflex or H-specific phase of reflexes reflex locomotion Spinal pathway ofSteady-state EMG EMG responses to Walking; cutaneous reflexes cutaneousnerve Withdrawal stimulation responses Corticospinal tract Steady-stateEMG First EMG response Walking; to electrical (rats) Hand/arm control ormagnetic (humans) stimulation of cortex Reciprocal Controlling EEG MeanSMR Reach-and-grasp; thalamocortical SMR amplitudes to amplitude beforeor Other discrete pathways that move a cursor to a during the period ofskilled actions produce EEG target on a screen cursor control to asensorimotor rhythms specific target (SMRs)

As shown in Table 1, the method, device, and system of the presentinvention can be used in numerous applications. In view of the presentdisclosure and teachings herein, those applications are understood bythose of ordinary skill in the art. For example, with regard tocutaneous reflexes, these are known to consist of several differentlatency components, just like stretch reflexes. Thus, the earliestresponse is not necessarily the most functional or meaningful in motorcontrol.

Devices and Systems for Improving Nervous System Function

In another aspect, the present invention provides a device for restoringor improving nervous system function of a subject. The device comprisesa nerve stimulation-electromyographic recording component and acontroller for operating the nerve stimulation-electromyographicrecording component in accordance with an operant conditioning protocol.The nerve stimulation-electromyographic recording component comprises anerve stimulator for stimulating a primary targeted central nervoussystem (CNS) pathway in a subject, at least one stimulating electrodearray in functional communication with the nerve stimulator and adaptedfor topical contact with the subject, and at least one electromyographic(EMG) recording electrode array for recording EMG data of the subjectproduced in response to the stimulation of the primary targeted CNSpathway. As mentioned, the device also comprises a controller foroperating the nerve stimulation-electromyographic recording component inaccordance with an operant conditioning protocol. The operantconditioning protocol is effective to produce targeted neural plasticity(TNP) in the primary targeted CNS pathway of the subject.

In another aspect, the present invention provides a system for restoringor improving nervous system function of a subject. The system comprisesthe device of the present invention in functional communication and/orin functional combination with any other apparatus, component, device,or system that enables the functioning of the device for use by asubject. The device of the present invention, which comprises the mainpart of any system of the present invention, is described in more detailherein and particularly below.

In various embodiments, a suitable nerve stimulator of the devicecomprises an apparatus for providing a current or voltage pulse ofselectable polarity, duration, and strength at externally triggeredtimes through a pair of skin-mounted electrodes selected from astimulating electrode array. In a particular embodiment, the at leastone stimulating electrode array comprises one or more possible pairs ofstimulating electrodes.

In various embodiments, the at least one EMG recording electrode arraycomprises one or more possible pairs of EMG recording electrode arrays.

In accordance with various embodiments of the device of the presentinvention, suitable operant conditioning protocols can include thosethat are effective to also elicit generalized neural plasticity (GNP) inone or more other CNS pathway, where the elicitation of the GNP in theone or more other CNS pathway serves to restore or improve a nervoussystem function of the subject.

As set forth herein, the device of the present invention also includes acontroller for operating the nerve stimulation-electromyographicrecording component of the device. In one embodiment, the controllercomprises a computer processor and corresponding software effective toperform the operant conditioning protocol on the subject. As set forthherein and below, the software for use with the device and thecontroller of the device can have various attributes and functions inthe operation of the device, system, and methods of the presentinvention.

In one embodiment, the software evaluates all possible pairs ofstimulating electrodes to choose the most effective pair. For example,the software can operate so that the pair of stimulating electrodeselicits a soleus muscle response (M-wave) at the lowest stimulus leveland does not elicit a response in another muscle (e.g., tibialisanterior).

In another embodiment, the software evaluates all possible pairs ofsoleus muscle recording electrodes to choose the most effective pair.For example, the software can operate so that the pair of soleus musclerecording electrodes detects a soleus muscle response at the loweststimulus level.

In another embodiment, the software automatically adjusts stimulusstrength as needed to maintain the target M wave. For example, thesoftware can automatically adjust stimulus strength between trial blocksto maintain the target M wave.

In another embodiment, the software automatically adjusts the amplitudecriterion for reward as needed to maintain an appropriate rewardfrequency. For example, the software can automatically adjust theamplitude criterion for reward between trial blocks to maintain anappropriate reward frequency.

In yet another embodiment, the software notifies the subject and/or atherapist via the internet of any problem in EMG recording, in theresponses obtained, or in other aspects of operation, and providesinstructions and oversight for resolving the problem. For example, thesoftware can notify the subject and/or a therapist via the internet ofany problem in EMG recording (e.g., non-EMG artifacts), in the responsesobtained, or in other aspects of operation, and provides instructionsand oversight for resolving the problem.

In various embodiments, the controller comprises a monitoring componenteffective to provide real-time feedback to the subject duringperformance of the operant conditioning protocol. Suitable monitoringcomponents can include any monitoring component that is effective toprovide visual real-time feedback, audio real-time feedback, both visualand audio real-time feedback, and/or other sensory real-time feedback tothe subject.

In various embodiments, the controller is in communication with thenerve stimulation-electromyographic recording component. Communicationbetween the controller and the nerve stimulation-electromyographicrecording component can be via a wireless or wired functionalconnection.

In other embodiments, the controller provides the subject with completeand appropriately illustrated instructions for donning and doffing thedevice, parameterizing the operant conditioning protocol, performing theoperant conditioning protocol, and handling associated details selectedfrom the group consisting of data storage, Internet-based interactionwith a therapist, and the like.

In certain embodiments, the device of the present invention furthercomprises a wearable placement component for positioning the at leastone stimulating electrode array at a stimulation target area of thesubject and/or for positioning the at least one EMG recording electrodearray at an EMG recording target area of the subject. Suitable examplesof wearable placement components can include, without limitation, anywrap device (e.g., a leg wrap, a wrist wrap, a shoulder wrap, a backwrap, etc.), a garment, or other means for holding the device in placefor use by the subject.

With regard to placement of the stimulating electrode arrays, in oneembodiment, the stimulation target area of the subject is an area of theskin of the subject suitable for stimulating the primary targeted CNSpathway in the subject.

With regard to the placement of the EMG recording electrode arrays, inone embodiment, the EMG recording target area of the subject is an areaof the skin of the subject suitable for facilitating the recording ofthe recording EMG data of the subject produced in response to thestimulation of the primary targeted CNS pathway.

In certain other embodiments, the device of the present inventionfurther comprises a wireless communication device for receiving,displaying, storing, and/or analyzing data generated by the controller.Suitable examples of a wireless communication device as used herein caninclude, without limitation, a computer, a computer tablet, a personaldigital assistant (PDA), a mobile phone, a portable digital mediaplayer, a personal eyewear apparatus for receiving and displaying datagenerated by the controller, and a dedicated digital device forreceiving and displaying the data generated by the controller. Inparticular examples, the personal eyewear apparatus can include in-eyedigital lenses (contact lenses with digital monitoring functionality) ora wearable computer with an optical head-mounted display (OHMD) such asthe product known as Google Glass. Other wearable wireless communicationdevices can be those that can be mounted on a garment or other item wornby the subject (e.g., a visor of a hat so that the subject can view adigital display).

The present invention also includes connected or wired (i.e., notwireless) communication devices as a means for receiving, displaying,storing, and/or analyzing data generated by the controller. Therefore,the present invention contemplates connected or wired wearablecommunication devices that correspond with any of the above wearablewireless communication devices, with the difference being the wiredconnection between the controller and the wearable communication device.

In various embodiments, the present invention provides a device forimproving nervous system function of a subject that is usable by thesubject in a home or other setting without expert assistance oroversight. The device is effective for performing the variousembodiments of the method of the present invention as described herein.In a particular embodiment, the device is effective in performing aparticular method of the present invention for improving walking inpeople in whom walking has been impaired by a spinal cord injury orother neuromuscular trauma or disease. Prior to the present invention,such a method required a cumbersome complex arrangement of laboratoryequipment (see FIG. 1) and the continuous active involvement andoversight of a highly skilled technician with specialized knowledge andexperience in clinical neurophysiology or closely related disciplines.In contrast, the device of the present invention is a highly compact,portable, and fully automated unit that can be used by a subjectindependently in the home without the involvement of an expert (see,e.g., FIG. 2). The therapist can oversee progress via the Internet andthrough occasional formal evaluations in the clinic. The deviceeliminates the complex cumbersome laboratory apparatus and accomplishesthrough novel software algorithms the essential steps that previouslyrequired the continual involvement and adjustments of a highly trainedexpert. It enables an affected individual to apply an appropriate reflexoperant conditioning protocol to produce targeted neural plasticity(TNP) that triggers widespread plasticity that restores more normalwalking.

In various embodiments, the device of the present invention translatesthe effective new therapeutic method already validated in rats and inhumans with spinal cord injuries into a clinically and commerciallypractical system that can significantly enhance recovery of functionbeyond that achievable with current neurorehabilitation regimens.Furthermore, this unit is readily usable by patients on a daily basiswithout close oversight, which allows frequent use with minimal demandon therapist time and effort. Device operation and results can bemonitored periodically through the Internet. The embodiment describedhere targets the soleus H-reflex. The device can also target otherspinal cord reflexes or brain-spinal cord connections.

As shown in FIG. 1, the prior art methods and devices required acumbersome laboratory system and setup. By way of contrast, as shown inFIG. 2, the present invention provides a device 16 that is compact,portable, and fully automated. FIG. 2 illustrates the device's physicalsimplicity and its ability to function without expert involvement oroversight. Its key hardware and software components and their functionsare described herein in more detail.

In various embodiments, to accomplish its essential functions, thedevice incorporates automated capacities for: selection of stimulationand recording sites; derivation of reflex recruitment curves; selectionand ongoing adjustment of stimulus parameters with absolute safeguardsagainst inappropriate stimulation; selection and ongoing adjustment ofoperant conditioning criteria; artifact detection and correction; datacollection and storage; Internet-based transmission of data andoperating parameters; and periodic or ad hoc two-way Internet-basedinteraction with a clinic-based therapist for data monitoring orparameter adjustment. This device consists of hardware and software.

In various embodiments of the device, the hardware includes: aprogrammable nerve stimulation-EMG (electromyographic) recording(NS-EMG) component that can be mounted (e.g., via a wrap) at a givenplace on the body (e.g., calf and knee) (see FIGS. 2 and 3); and a videoscreen (i.e., the interface). These two parts can communicate viatelemetry (i.e., the cloud).

In a particular embodiment, the programmable NS-EMG component hasvarious component parts, including, without limitation, those describedas follows: A flexible comfortable wrap that can be fixed in place at aspecific orientation over the knee and calf can be used. It can beadjustable to limb size. Embedded in the wrap can be an array of smallstimulating electrodes that contact the skin in the popliteal fossa(i.e., behind the knee) (see FIG. 3). Embedded in the wrap can also be aground electrode that contacts the skin of the knee cap (i.e., the frontof the knee) (see FIG. 3). Embedded in the wrap can also be an array ofsmall EMG recording electrodes that contact the skin over the soleusmuscle (i.e., middle and lower posterior calf) (see FIG. 3). Embedded inthe wrap can further be an array of small EMG recording electrodes thatcontact the skin over the tibialis anterior muscle (i.e., middleanterior calf) (see FIG. 3). An externally programmable bipolar nervestimulator capable of delivering 1-50 mA, 0.1-2.0 ms pulses at intervalsof 100 ms or more and approved for human use can be embedded in thedevice. An electronic multi-channel switch that connects a programmableset of stimulation electrodes to the positive and negative outputs ofthe nerve stimulator can be embedded in the device. An electronicmulti-channel switch that connects a programmable set of recording andstimulating electrodes to the EMG amplifier can be embedded in thedevice. A multichannel EMG amplifier and digitizer, connected to themultichannel recording/stimulation switch, can be embedded in thedevice. This amplifier and digitizer are able to record from 64electrodes (i.e., 32 bipolar channels). The amplifier and digitizer areable to record the ongoing EMG activity, the stimulation artifact, andthe subsequent EMG response. A wireless two-way low-power interface(IEEE 802.11b/g/n, Bluetooth 4.0) can be used to connect the device tothe cloud and the user interface. The QOS settings of the wirelessinterface ensure a round-trip time of <200 ms, which allows the NS-EMGdevice to function properly.

In some embodiments, initial configuration of the NS-EMG device iseither performed through paring the NS-EMG device with an iOS or Androiddevice over a Bluetooth ad-hoc connection or through connecting to aWindows or Macintosh PC via a USB connection. The iOS, Android, Windowsor Macintosh devices run proprietary software that configures theconnection of the NS-EMG device to the cloud. This includes the WiFiSSID name and WEP, WPA, WPA2, WPA-personal, WPA-enterprise keys formultiple wireless IEEE 802.11b/g/n networks. Once the NS-EMG device isfully configured it will connect automatically to any wireless networkthat was previously configured.

In some embodiments, the NS-EMG device functions together with a legwrap, disposable electrodes, a programmable controller, a video screen,a cloud service and a wireless network (see FIGS. 2-6).

In some embodiments, the NS-EMG device can be distributed over thecounter with supplies (i.e., 200 disposable electrode array sets), amanual and video instructions.

The NS-EMG device can operate autonomously or under supervision of aclinician or therapist in a clinic or through a subscription service.

The programmable controller and video screen component performs thefollowing functions without human intervention or guidance:

It provides information and instructions to the device user regardingeach step in the protocol. The video display shows the subject how todon the device and initiate operation; and it leads the subject througheach step in the selection of recording and stimulating electrodes, theselection of the background EMG range, the derivation of the M-wave andH-reflex recruitment curves, and the performances of control andconditioned H-reflex trials.

In various embodiments, it selects the stimulating and recordingelectrode pairs. Using a short (e.g., 1-50 mA, 1-msec) square-wavestimulus pulse, it begins at a subthreshold stimulation level and cyclesthrough the possible stimulating electrodes (and both polarities of eachpair) at a brisk rate (e.g., 0.5 Hz) while monitoring all recordingelectrode pairs; and it raises stimulus amplitude in small incrementsuntil a threshold M-wave is reliably obtained. The stimulating electrodepair and polarity that elicits and the recording electrode pair thatdetects, respectively, that response are selected to be usedthenceforth.

In various aspects, it is understood that, if the stimulation rate istoo high, postactivation depression of the H-reflex will get in the wayto detect an optimum stimulus location. In the active muscle (i.e., withbackground EMG activity), 0.5 Hz stimulation won't induce postactivationdepression. In a resting muscle, it will (postactivation depression canbe observed up to 0.1 Hz).

In various embodiments, it determines the EMG level that corresponds toa maximum voluntary contraction (MVC) (measured as absolute value of EMG(i.e., rectified EMG)). It asks the subject to produce a MVC for about 3sec, and repeats this request several (e.g., 3) times at a minimuminterval of about 1 min. In various embodiments, a longer interval than1 min can be used to obtain MVC correctly. However, 1 min can be viewedas the minimum in various embodiments. It determines the averageabsolute value for the middle 2 sec of each MVC and averages the highestthree values of the four MVCs to determine the MVC. The background EMGlevel required during H-reflex trials is defined as a fixed range inpercent (e.g., 10-20%) of this MVC (or, alternatively, as a specificrange in μV).

In various embodiments, it identifies the time windows in the EMGfollowing nerve stimulation that reflect, respectively, the effectivestimulus strength (Window A) (e.g., the M-wave) and the strength of theresponse of the nervous system pathway to be modified (Window B) (e.g.,the H-reflex). It defines the M-wave window from EMG responses toseveral times (e.g., twice) M-threshold stimulation at a rate of about0.5 Hz. It defines the H-reflex window based on the standard H-reflexlatency range and the responses to 1-2×M-threshold stimulation at 0.2 Hzin the presence of a correct background EMG level (as defined above andherein).

In various embodiments, it elicits a Window A/Window B recruitmentcurve. It obtains this M-wave/H-reflex recruitment curve in the presenceof the required background EMG level. It begins below M-wave thresholdand gradually increases the stimulus to Mmax, stimulating about 4 timesat each stimulus level at a rate of 0.2 Hz. Based on the results, itselects a target M-wave (i.e., Window A) amplitude and a correspondingstimulus level for the H-reflex trials.

In various embodiments, in initial sessions (i.e., Baseline sessions) ituses the chosen stimulating and recording electrodes and the selectedstimulus amplitude to conduct several (e.g., 3) control H-reflexelicitation blocks (e.g., 75 trials each). In each trial, the H-reflexis elicited after the subject maintains background EMG in the requiredrange for several sec.

During these blocks of control trials, it provides visual (and/or othersensory) feedback to the user of current EMG background level versus therequired range. For example, a graph on the video screen displays thecurrent EMG level as a vertical bar superimposed on the requiredbackground range; the bar is green when it falls in the range and redwhen it does not.

In various embodiments, it may also provide more complex sensoryfeedback, such as in the context of a game that actively engages thesubject and motivates the subject to use the device more often and formore trials, and thereby augments the production of generalized neuralplasticity (GNP) and its beneficial effects on CNS function. Thus, itmay complement and enhance conventional rehabilitation and trainingregimens by motivating activities that engage the most relevant nervoussystem pathways.

In various embodiments, it stores complete EMG data for each stimulation(i.e., each trial).

In various embodiments, throughout the baseline sessions, itperiodically adjusts the stimulus level to maintain the target M-waveamplitude.

In various embodiments, it calculates average Window A (M-wave) andWindow B (H-reflex) amplitudes for all baseline sessions. Thedistribution of H-reflex amplitudes is used to determine the initialreward criterion value for the conditioning sessions (e.g., if the goalis to make the H-reflex larger, the criterion might be set so that thelargest 60% of the H-reflexes satisfy it).

In various embodiments, in subsequent H-reflex conditioning sessions, ituses the chosen stimulating and recording electrodes to conduct a blockof about 20 control H-reflex elicitation trials followed by three blocks(e.g., 75 trials each) of conditioning H-reflex trials. In each controlor conditioning trial, the H-reflex is elicited after the subjectmaintains background EMG in the required range for several sec.

In addition, in various embodiments, in conditioning trials only, thesubject is provided immediate feedback indicating whether the H-reflexsize satisfied the criterion value. A second graph on the video screendisplays H-reflex size as a vertical bar and the current H-reflexcriterion value as a superimposed range (i.e., above or below a givenvalue). The bar is green when H-reflex size falls in the range and redwhen it does not.

In various embodiments, throughout the conditioning sessions, itperiodically adjusts stimulus amplitude to maintain the target M-waveamplitude.

In various embodiments, between the trial blocks of the conditioningsessions, it adjusts the H-reflex amplitude criterion to maintain anappropriate reward probability (e.g., 60%).

In various embodiments, it continues to store all trial data for lateranalysis and summary.

It interacts via the Internet with a remote site for data transfer.Following each session and/or whenever requested remotely by atherapist, it sends complete data and all current parameters to thetherapist via the Internet. In addition, it accepts changes inparameters (e.g., target reward probability) from the therapist.

Exemplary Embodiments of Devices and Systems for Improving NervousSystem Function

For illustrative purposes, provided below are descriptions of exemplaryembodiments of devices and systems for improving nervous system functionas provided by the present invention and as performed in accordance withmethods of the present invention. More particularly, below are furtherdescriptions of the exemplary embodiments of the present invention asshown in FIGS. 2-6.

For context, reference is made to FIG. 1, which is an illustration of astandard laboratory set-up for operant conditioning of the soleusH-reflex. As shown in FIG. 1, in standard operant conditioning of thesoleus H-reflex, a trained therapist is needed to assist with theprocess. Further, large equipment set-ups are used during the process,and the subject is hooked to such equipment during the process.

By way of the contrast, as shown in FIG. 2, the device, system, and/ormethod of the present invention do not require large equipment or atrained therapist to be present during the procedure. FIG. 2 is anillustration one embodiment of a spinal reflex operant conditioningsystem as disclosed herein. As described above, no therapist or systemoperator is necessary. The electronics and the computer shown in therack in FIG. 1 are incorporated into the pocket shown in the lower legwrap (16), and they communicate via telemetry with a cloud service andthe user interface (i.e., the monitor on the table in front of thesubject).

As shown in FIG. 3, in one embodiment, device 17 is in the form of a legwrap. As shown in FIG. 3, the leg wrap includes a popliteal simulatingelectrode array (“stimulation array”) and a soleus muscle recordingelectrode array (“recording array”), as well as a “ground” electrode.

As shown in FIG. 4, in one embodiment, the present invention provides anerve stimulation-electromyographic (NS-EMG) device that compriseselectronics that can be embedded in a pocket of a leg wrap embodiment ofdevice 17 shown in FIG. 3. As shown, in various embodiments, the NS-EMGdevice can be encased in a waterproof (IPX-7) plastic case 18.

Referring to FIG. 4, the NS-EMG device can contain the following: One3.8V, 10 W lithium-polymer battery 19. One single stream 802.11-a/b/g/nantenna 20. One Bluetooth antenna 21. An analog processing unit 22 thatrecords from and stimulate surface electrodes. The recording unit canconsist of a programmable multichannel switch that selects a set of 64electrodes, and an amplifier/digitizer that translates the selectedchannels into digital values. The stimulation unit can consist of aprogrammable multichannel switch that connects a set of electrodes tothe positive and negative output of a nerve stimulator. The programmablehuman-rated nerve stimulator can output 1-50 mA 0.1-2.0 msec currentpulses.

Referring again to FIG. 4, the NS-EMG device can contain the following:A digital processing unit 23 that processes the digitized signals andperforms the stimulation paradigm where the digital processing unitcommunicates with the NS-EMG cloud service and the user interface overTCP/IP and HTML5 protocols. The NS-EMG device also can contain, as shownin FIG. 4, a digital storage unit 24 that stores the firmware and therecorded EMG data. The data is periodically uploaded to the NS-EMG cloudservice. As shown in FIG. 4, the NS-EMG device can also be powered onand off via a push button 25 on the side of the plastic case. Pushingthe button for more than 7 sec powers the device on/off. Pushing thebutton for less than 7 sec can show battery indicator lights 26. TheNS-EMG device can be charged via a micro-USB port 27 on the bottom ofthe device. To ensure safety, operation of the device can be suspendedwhile being charged. The NS-EMG device can be connected via a flatribbon cable to the electrodes, as shown in FIG. 4 as drawing referencenumber 28.

Referring to FIG. 5, in one embodiment, the present invention provides adevice, method, and system that uses a portable device that communicateswith the Internet via the cloud. FIG. 5 shows one embodiment of aninitial set-up and subsequent communication of a device of the presentdisclosure with a cloud service and a user interface. As shown in FIG.5, the NS-EMG device is initially configured over an ad-hoc pairedBluetooth Connection to an iOS, Android or Windows Phone compatibledevice (30). In this initial setup, the connection and user parametersare set. The connection parameters include the SSID andWEP/WPA/WPA2/WPA2-personal/WPA2-enterprise encryption keys for the802.11-a/b/g/n networks to which the NS-EMG device connects. The userparameters include the username and password for the NS-EMG cloudservice. The NS-EMG device automatically connects to any initiallyconfigured 802.11a/b/g/n WiFi network (31). The NS-EMG deviceautomatically registers with the NS-EMG cloud service upon connecting toa WiFi network (32). The user receives visual feedback on a HTML5capable personal computer, tabled or phone (33). On this device the userconnects to the NS-EMG cloud service using his username and password.The HTML5 interface is received from the cloud while the feedback valuesare directly received from the NS-EMG device, therefore ensuring the<200-ms real-time performance of the visual feedback (34). The clinicianreceives a summary of the training performance on a HTML5 capablepersonal computer, tablet, or phone (35). The interface to the clinicianand all summary values are provided by the NS-EMG cloud service. Allinformation is provided in a HIPAA compliant fashion.

Referring to FIG. 6, in one embodiment there is provided a systemincluding stimulation and recording of the nerve stimulation andelectromyographic (EMG) recording interfaces. As shown in FIG. 6, thesystem can include a programmable multichannel switch that connects asubset of the stimulation electrodes to the positive and negative outputof the nerve stimulator (37). The programmable nerve stimulator deliverssingle or trains of 1-50 mA current pulses that have a duration of about1 ms and are triggered by the protocol (38). A programmable multichannelswitch selects up to 64 of the stimulation and recording channels forthe digitization step (39). The digitization step amplifies, bandpassfilters and converts the signal into digital values at a rate of 2 kHz(40).

EXAMPLES

The following examples are intended to illustrate particular embodimentsof the present invention, but are by no means intended to limit thescope of the present invention.

Example 1 Operant Conditioning of Rat Soleus H-Reflex Oppositely AffectsAnother H-Reflex and Changes Locomotor Kinematics Overview

H-reflex conditioning is a model for studying the plasticity associatedwith a new motor skill. We are exploring its effects on other reflexesand on locomotion. Rats were implanted with EMG electrodes in both solei(SOL_(R) and SOL_(L)) and right quadriceps (QD_(R)), and stimulatingcuffs on both posterior tibial (PT) nerves and right posterior femoralnerve. When SOL_(R) EMG remained in a defined range, PT_(R) stimulationjust above M-response threshold elicited the SOL_(R) H-reflex. Analogousprocedures elicited the QD_(R) and SOL_(L) H-reflexes. After a controlperiod, each rat was exposed for 50 days to a protocol that rewardedSOL_(R) H-reflexes that were above (HRup rats) or below (HRdown rats) acriterion.

HRup conditioning increased the SOL_(R) H-reflex to 214(±37 SEM) % ofcontrol (P=0.02) and decreased the QD_(R) H-reflex to 71(±26) %(P=0.06). HRdown conditioning decreased the SOL_(R) H-reflex to 69(±2) %(P<0.001) and increased the QD_(R) H-reflex to 121(±7) % (P=0.02). Thesechanges remained during locomotion. The SOL_(L) H-reflex did not change.During the stance phase of locomotion, ankle plantarflexion increased inHRup rats and decreased in HRdown rats, hip extension did the opposite,and hip height did not change.

The plasticity that changes the QD_(R) H-reflex and locomotor kinematicsmay be inevitable (i.e., reactive) due to the ubiquity ofactivity-dependent CNS plasticity, and/or necessary (i.e., compensatory)to preserve other behaviors (e.g., locomotion) that would otherwise bedisturbed by the change in the SOL_(R) H-reflex pathway. The changes injoint angles, coupled with the preservation of hip height, suggest thatcompensatory plasticity did occur.

The present study is the first effort to determine whether soleusH-reflex conditioning affects the H-reflex of a hindlimb muscle group(i.e., quadriceps (QD)) that operates about different joints (i.e., kneeand hip rather than ankle), and whether it affects joint angles duringlocomotion. The data show that soleus H-reflex conditioning has amarkedly different effect on the QD H-reflex and produces distinctivemulti joint kinematic changes during locomotion. They indicate that theacquisition of an ostensibly simple new skill has an impact that extendsbeyond the new skill to affect a crucial older skill, and they raiseimportant new questions.

Materials and Methods

Twenty-six male Sprague-Dawley rats (439(±44 SD) g initially) werestudied. All procedures satisfied the “Guide for the Care and Use ofLaboratory Animals” (National Academy Press, Washington, D.C., 2011),and had been approved by the Wadsworth Center Institutional Animal Careand Use Committee. The methods have been fully described previously(Chen and Wolpaw 1995, 2002; Chen et al. 2005, 2006a, 2006b) and aresummarized here.

Electrode Implantation

Under general anesthesia (ketamine HCl (80 mg/kg) and xylazine (10mg/kg) (both i.p.) or sodium pentobarbital (60 mg/kg, i.p.),supplemented as needed) and aseptic conditions, each rat was implantedwith chronic stimulating and recording electrodes in the right and leftlegs. To elicit H-reflexes in the right and left solei (SOL_(R) andSOL_(L)), cuffs were placed on the right and left posterior tibial(PT_(R) and PT_(L)) nerves just above the triceps surae branches. Toelicit the H-reflex of the right quadriceps muscle group (QD_(R)), asimilar cuff was placed on the right posterior division of the femoral(PF_(R)) nerve. To record SOL_(R), SOL_(L), and QD_(R) EMG, a pair ofstainless steel fine-wire electrodes was implanted in each. The soleusacts about the ankle joint to plantarflex the foot. The QD groupcomprises four muscles: vastus lateralis, medialis, and intermedialis,and rectus femoris. All four act about the knee to dorsiflex (i.e.,extend) the calf, and the rectus femoris also acts about the hip to flexthe thigh (i.e., to move it forward and up). The two QD_(R) EMGelectrodes were placed laterally (targeting vastus lateralis) andmedially (targeting vastus medialis), respectively, so that their datawould represent the entire QD muscle group. The Teflon-coated wires fromall the electrodes passed subcutaneously to a connector on the skull.

After surgery, the rat was placed under a heating lamp and given ananalgesic (Demerol, 0.2 mg, intramuscular). Once awake, it received asecond dose of analgesic and was returned to its cage and allowed to eatand drink freely.

Experimental Design and SOL_(R) H-Reflex Conditioning

Data collection began at least 20 days after surgery and continued 24hrs/day, 7 days/week for at least 70 days. During this period, the ratlived in a standard rat cage with a 40-cm flexible cable attached to theskull connector. The cable, which allowed the animal to move freelyabout the cage, connected to a commutator above the cage that connectedto EMG amplifiers (gain 1000, bandwidth 100-1000 Hz) and the nerve-cuffstimulation units. The rat had free access to water and food, exceptthat during H-reflex conditioning it received food mainly by performingthe task described below. Animal well-being was carefully checkedseveral times each day, and body weight was measured weekly. Laboratorylights were dimmed from 2100 to 0600 daily.

Stimulus delivery and data collection were controlled by a computer,which sampled (5 kHz) SOL_(R), SOL_(L), and QD_(R) EMG continuously forthe entire period of study. SOL_(R) and SOL_(L) H-reflexes were elicitedsimultaneously as follows. Whenever the absolute value (i.e., thefull-wave rectified value) of background (i.e., ongoing) EMG in eachmuscle remained within a pre-defined range for a randomly varying2.3-2.7 s period, the computer initiated a trial. In each trial, thecomputer stored the most recent 50 ms of EMG from all three muscles(i.e., the background EMG window), delivered simultaneous monophasicstimulus pulses through the cuffs on the PT_(R) and PT_(L) nerves, andstored the EMG from all muscles for another 100 ms. A comparableprocedure elicited the QD_(R) H-reflex by stimulating the PF_(R) nervewhenever ongoing QD_(R) EMG remained within a pre-defined range. BecauseSOL and QD H-reflex trials occurred only when the muscles satisfiedtheir background EMG requirements, SOL and QD H-reflex trials seldomoccurred in close proximity to each other.

Stimulus pulse amplitude and duration were initially set to produce amaximum H-reflex (and an M wave that was typically just above threshold)in the muscle served by the stimulated nerve. Pulse duration remainedfixed (typically 0.5 ms). After each trial, pulse amplitude was adjustedautomatically to maintain the M wave (i.e., average EMG amplitude in theM wave window (typically 2.0-5.0 ms in SOL_(R) and SOL_(L) and 1.5-4.5ms in QD_(R))) unchanged throughout data collection. (This ensured thatthe effective strength of the stimulus was stable throughout (Wolpaw1987; Chen and Wolpaw 1995).) H-reflex size was defined as average EMGamplitude in the H-reflex window (typically 6-10 ms in SOL_(R) andSOL_(L) and 4.5-8.5 ms in QD_(R)) minus the muscle's average backgroundEMG amplitude.

Under the control mode, the computer simply digitized and stored the EMGfrom each muscle for 100 ms following the stimulus. Under the SOL_(R)up-conditioning (HRup) or down-conditioning (HRdown) mode, it also gavea food-pellet reward 200 ms after the PT_(R) nerve stimulation if theaverage amplitude of SOL_(R) EMG in the H-reflex window was above (HRup)or below (HRdown) a criterion. The criterion was set and adjusted dailyas needed, so that the rat received an adequate amount of food (about1000 pellets/day for a 500-gm rat).

Each rat was first studied under the control mode for about 20 days. Itwas then exposed to SOL_(R) up-conditioning (HRup rats) ordown-conditioning (HRdown rats) for 50 days. The last 10 control-modedays and the last 10 HRup or HRdown days (i.e., days 41-50 ofconditioning) provided the data used to assess the impact of SOL_(R)H-reflex conditioning on SOL_(R), QD_(R), and SOL_(L) H-reflexes.

H-Reflex and Kinematic Measurements During Treadmill Locomotion

SOL_(R) and QD_(R) locomotor H-reflexes and right hindlimb kinematicswere studied in two treadmill sessions, one during the control-mode daysand one near the end of SOL_(R) HRup or HRdown conditioning. Treadmillspeed was the same in both sessions (typically 10-12 m/min), and EMG wascontinuously recorded (0.1-1.0 kHz bandpass), digitized (4.0 kHz), andstored. In each session, reflex data were collected for two 4-5 minperiods. In one, the PT_(R) nerve was stimulated to elicit the SOL_(R)H-reflex, and in the other the PF_(R) nerve was stimulated to elicit theQD_(R) H-reflex. The nerve was stimulated when its muscle's EMG hadremained in a specified high range for 200 ms. Thus the stimulustypically occurred in the later part of the right stance phase of thestep cycle (about 100 ms past the middle of the muscle's locomotorburst). Stimulus amplitude was kept just above M-response threshold asdescribed above. (H-reflex elicitation during stance meant that thereflex was measured at a time when its pathway is likely to affectlocomotion.) In addition, the rat was videotaped (60 wraps/sec) from theright side during 4-5 min of treadmill walking without nervestimulation.

Those trials for which SOL_(R) or QD_(R) EMG amplitude for the 20 msimmediately before the stimulus and M-response size satisfied specifiedcriteria were averaged by triggering on the stimuli. Thus, the averagepre-stimulus EMG amplitudes and M-response sizes were the same for thetwo treadmill sessions.

In video analysis, we identified the right stance-phase images and,using marks on the ankle, knee, and hip, calculated for the entirestance phase the average anterior hip angle (i.e., hip extension: theangle of the thigh to a horizontal line projecting forward from thehip), posterior knee angle, and anterior ankle angle (i.e., ankleplantarflexion), and the average height of the hip above the treadmillsurface.

Statistical Analysis

The data fell into three categories. The first category consisted ofSOL_(R), QD_(R), and SOL_(L) H-reflexes elicited under the conditioningprotocol, that is, throughout the day as the rat moved freely about itshome cage. These are henceforth called “conditioning H-reflexes.”Thesecond category consisted of SOL_(R) and QD_(R) H-reflexes during theright stance phase of locomotion. These are called “locomotorH-reflexes.” The third category consisted of average right stance-phaseankle, knee, and hip angles and average hip heights.

For each conditioning reflex, a paired t-test compared the average valuefor the last 10 days of SOL_(R) HRup or HRdown conditioning to that forthe last 10 control-mode days. For each locomotor reflex and joint angleand for hip height, a paired t-test compared the value for the secondtreadmill session to that for the first treadmill session.

Animal Perfusion and Anatomical Study

At the end of study, each rat received an overdose of sodiumpentobarbital (i.p.) and was perfused through the heart. The EMGelectrodes, nerve cuffs, and PT and PF nerves were examined and the SOLmuscles of both sides were removed and weighed.

Results

Animals remained healthy and active throughout study. Body weightincreased from 439(±44 SD) g at implantation to 568(±54) g at perfusion.In all rats, postmortem examination found that the cuffs were in placeand covered by connective tissue, and that the nerves were wellpreserved. SOL_(R) and SOL_(L) weights did not differ significantly, nordid they differ from those of 113 normal rats previously studied.

Effects of SOL_(R) H-Reflex Conditioning on SOL_(R), QD_(R), and SOL_(L)Conditioning H-Reflexes

To determine the final effect on each muscle's conditioning H-reflexsize of SOL_(R) HRup or HRdown conditioning, the muscle's averageH-reflex size for the final 10 days of conditioning was calculated aspercent of its initial H-reflex size (i.e., average of final 10control-mode days). As in previous studies, successful SOL_(R) H-reflexconditioning was defined as a change ≧20% in the correct direction. Bythis criterion, SOL_(R) H-reflex conditioning was successful in 9 HRupand 8 HRdown rats. In the remaining rats (4 HRup and 5 HRdown), thefinal SOL_(R) H-reflex was within 20% of its initial value.

FIG. 7 shows the average final values (±SEM) of SOL_(R), QD_(R), andSOL_(L) H-reflexes, M waves, and background EMG in the successful HRup(left) and HRdown (right) rats in percent of their initial values. Inaccord with the goal of the conditioning protocol, the final SOL_(R)H-reflex is markedly and significantly increased in HRup rats (P=0.02,paired t-test) and decreased in HRdown rats (P<0.001). In contrast,SOL_(R) HRup or HRdown conditioning oppositely affected the QD_(R)H-reflex: the final QD_(R) H-reflex appears to be smaller in SOL_(R)HRup rats (P=0.06), and is larger in SOL_(R) HRdown rats (P=0.02). Atthe same time, neither SOL_(R) HRup or HRdown conditioning has anoticeable effect on SOL_(L) H-reflexes. In all rats, M waves andbackground EMG do not change.

FIG. 8 shows initial and final SOL_(R) and QD_(R) H-reflexes for an HRuprat (left) and an HRdown rat (right). In the HRup rat, the SOL_(R)H-reflex is markedly larger after conditioning while the QD_(R) H-reflexis smaller. Conversely, in the HRdown rat, the SOL_(R) H-reflex is muchsmaller after conditioning while the QD_(R) H-reflex is larger.

Effects of SOL_(R) H-Reflex Conditioning on SOL_(R) and QD_(R) LocomotorH-Reflexes

In 7 of the 9 successful HRup rats and 6 of the 8 successful HRdownrats, SOL_(R) and QD_(R) locomotor H-reflexes were also studied duringthe stance phase of locomotion before and after SOL_(R) H-reflexconditioning. For these rats, FIG. 9A shows average final values (±SEM)of SOL_(R) and QD_(R) locomotor H-reflexes in percent of their initialcontrol values. SOL_(R) H-reflex conditioning has effects on the SOL_(R)and QD_(R) locomotor H-reflexes comparable to its effects on theconditioning H-reflexes. Indeed, the effects on the locomotor H-reflexesare even more prominent. Final SOL_(R) locomotor H-reflexes are markedlyand significantly increased in HRup rats (P=0.004) and decreased inHRdown rats (P=0.01). In contrast, SOL_(R) HRup or HRdown conditioninghas an opposite effect on the QD_(R) locomotor H-reflex: it appears tobe smaller in SOL_(R) HRup rats (P=0.07) and is significantly larger inSOL_(R) HRdown rats (P=0.004).

FIG. 9B shows initial and final SOL_(R) and QD_(R) locomotor H-reflexesfor one HRup rat (left) and one HRdown rat (right). In the HRup rat, theSOL_(R) H-reflex is markedly larger after conditioning while the QD_(R)H-reflex is smaller. Conversely, in the HRdown rat, the SOL_(R) H-reflexis smaller after conditioning while the QD_(R) H-reflex is larger.

In the unsuccessful rats, final SOL_(R) and QD_(R) locomotor H-reflexesvaried widely across animals. The SOL_(R) locomotor H-reflex actuallyincreased in 3 of the 5 unsuccessful HRdown rats, despite the fact thatthe SOL_(R) conditioning H-reflex did not change in any of them. Thisresult is consistent with an earlier study (Chen et al., 2005), andsuggests that the lack of change in the conditioning H-reflex does notnecessarily mean that conditioning has had no impact (Chen et al. (2005)for discussion).

Effects of SOL_(R) H-Reflex Conditioning on Ankle, Knee, and Hip Anglesand Hip Height

In 5 successful HRup rats and 6 successful HRdown rats, average rightankle, knee, and hip angles and hip height during the stance phase oftreadmill locomotion were determined before and after SOL_(R) H-reflexconditioning. FIG. 10 shows, for each rat, the final values (±SEM) ofthese measures in percent of their initial values. In HRup rats, finalanterior ankle angles were larger (P=0.04) (i.e., the ankle was moreplantarflexed) and final anterior hip angles tended to be smaller (i.e.,the hip was less extended) (P=0.13). In contrast, in HRdown rats, finalankle angles were smaller (P=0.008) and final hip angles were larger(P=0.03). Neither HRup nor HRdown conditioning significantly affectedknee angle or hip height.

Discussion

Operant conditioning of the rat SOL_(R) H-reflex has an opposite effecton the QD_(R) H-reflex: in SOL_(R) HRup rats the QD_(R) H-reflex usuallygoes down, and in SOL_(R) HRdown rats the QD_(R) H-reflex goes up. TheseQD_(R) H-reflex changes, like the SOL_(R) changes, are still present,perhaps even greater, during locomotion. They occur despite the factthat they do not affect reward probability; the QD_(R) H-reflex iselicited at different times from the SOL_(R) H-reflex and is neverassociated with a reward. Nevertheless, it changes. Furthermore, SOL_(R)H-reflex conditioning has effects on ankle angle during locomotion thatare consistent with the SOL_(R) H-reflex changes; and, in addition, ithas opposite effects on hip angle, the etiology of which is not known atpresent.

The Plasticity Responsible for Change in the QD_(R) H-Reflex

The QD_(R) H-reflex is the earliest possible CNS-mediated QD response tothe PF_(R) nerve stimulus. Thus, the changes in QD_(R) H-reflex sizeassociated with SOL_(R) H-reflex conditioning could reflect plasticityin the reflex pathway itself or plasticity in neurons or synapses thatprovide tonic input to the pathway, input that is there before the nervestimulus. At present, evaluation of these two possibilities rests mainlyon what is known about the change in the H-reflex that controls thereward (i.e., the conditioned H-reflex).

Physiological and anatomical studies (reviewed in Wolpaw and Chen 2009;Wolpaw 2010) indicate that the change in the reflex being conditioned(i.e., the SOL_(R) H-reflex) is due mainly to plasticity in themotoneuron and/or the afferent pathway from the nerve stimulus, and thatthis plasticity is caused by change in corticospinal tract (CST)activity (which may pass through GABAergic interneurons in spinallaminae 6 and 7). For example, down-conditioning appears to be duemainly to a positive shift in motoneuron firing threshold (Carp andWolpaw 1994). Furthermore, the change in the conditioned reflex is stillevident when tonic inputs are greatly reduced or entirely eliminated(Wolpaw and Lee 1989). These findings suggest that the QD_(R) H-reflexchange reflects comparable plasticity in the QD_(R) H-reflex pathway.This conclusion is supported by the fact that the QD_(R) H-reflex changeis still evident during locomotion, which would be expected to modifytonic inputs.

The Etiology of the Change in the QD_(R) H-Reflex and in Hip Angle

The plasticity that changes the QD_(R) H-reflex or hip angle might occurin two ways. First, it might be an inevitable consequence of the factthat the capacity for activity-dependent plasticity is ubiquitous in theCNS. For example, the same CST activity that changes the SOL_(R)H-reflex pathway might also produce an opposite change in the QD_(R)H-reflex pathway. Such inverse effects on different muscles can occurwith supraspinal lesions (e.g., Thompson et al. 2009b). Furthermore, theplasticity in the SOL_(R) H-reflex pathway, by changing ongoing activityin intraspinal pathways, might itself induce plasticity in the QD_(R)H-reflex. Comparable plasticity in spinal pathways that affect hipmuscles might account for the change in hip angle. Plasticity created insuch ways reflects the activity-dependent properties of individualneurons and synapses. Thus, its etiology is local, and it can be called“reactive” plasticity (Wolpaw 1997). A simple example of reactiveplasticity is synaptic desensitization caused by increased synapticinput (e.g., Otis et al. 1996).

The second possible etiology of the QD_(R) H-reflex change or the hipangle change is that it is adaptive, that it helps to compensate for theimpact of SOL_(R) H-reflex conditioning on other behaviors. Because thespinal cord is the final common pathway for many behaviors, theplasticity in the SOL_(R) H-reflex pathway that increases rewardprobability affects other behaviors that also use this pathway. Indeed,SOL_(R) H-reflex conditioning can be used to improve locomotion after apartial spinal cord injury (Chen et al. 2006b). In normal rats withnormal locomotion, such side effects of H-reflex conditioning may induceadditional activity-dependent plasticity that preserves normallocomotion (or other important behaviors). Chen et al. (2005) found thatconditioning of the SOL_(R) H-reflex changed SOL locomotor activity, butdid not affect step-cycle length or symmetry, suggesting that otherchanges had preserved these major parameters of the step-cycle. Thisadditional plasticity can be called “compensatory” (Wolpaw 1997). Unlikereactive plasticity, which originates locally, compensatory plasticityis induced and shaped by interactions between the CNS and the externalworld (Wolpaw 2010 for discussion).

The present kinematic results suggest that SOL_(R) H-reflex conditioningdoes produce compensatory plasticity. SOL_(R) H-reflex conditioning hadeffects on stance-phase ankle plantarflexion that are consistent withthe SOL_(R) H-reflex change: increase in HRup rats and decrease inHRdown rats. At the same time, it had opposite effects on hip extension:decrease in HRup rats and increase in HRdown rats. These oppositechanges in hip angle appear to explain why hip height was notsignificantly changed despite the changes in ankle angle (i.e., FIG.10).

A unilateral change in hip height during locomotion would presumablytwist the thorax, which would probably have widespread short-term andlong-term musculoskeletal effects. Nociceptive or other sensory inputsproduced by this twisting might operantly condition compensatoryplasticity that eliminates the twisting and preserves hip height. Thus,like step-cycle symmetry (Chen et al. 2005), hip-height symmetry duringlocomotion may be a functionally important parameter; and anintervention that disrupts it, such as SOL_(R) H-reflex conditioning(which changes stance-phase foot plantarflexion), may inducecompensatory plasticity that prevents the disruption. Whether the changein hip angle does reflect compensatory plasticity, whether reflexchanges account for it, and why knee angle does not change instead (orin addition), are questions that will hopefully be elucidated by thecomprehensive kinematic and reflex studies now underway (Liu et al.2010).

Therapeutic Applications of Spinal Reflex Conditioning

H-reflex conditioning can improve locomotion in rats after a partialspinal cord injury (Chen et al. 2006b). Initial studies suggest that itcan be effective in humans with spinal cord injuries, and they indicatethat it requires only a small fraction of the conditioning trialsnormally used in animals (Pomerantz et al. 2010, Thompson et al. 2009a).The ability to target specific pathways could enable reflex conditioningprotocols to supplement other therapeutic interventions such aslocomotor training (Harkema et al. 2011). These protocols could beparticularly useful when spinal cord regeneration becomes possible andmethods are needed for guiding plasticity to produce a functionallyeffective spinal cord.

In the context of such therapeutic possibilities, the present resultsare both sobering and encouraging. They indicate the complexity of theeffects that might accompany this new approach. At the same time, bysuggesting that the plasticity induced by reflex conditioning may targetthe preservation (or restoration) of important functional parameters(e.g., hip height), they encourage further exploration of itstherapeutic applications.

Conclusions

Soleus H-reflex conditioning also affects the H-reflex of the quadricepsmuscle group, which operates about different joints, and it changeslocomotor kinematics at both the ankle and the hip. The quadricepsH-reflex change remains evident during locomotion, and is probably dueto plasticity in that H-reflex pathway. The change in hip angle islikely to reflect compensatory plasticity that preserves hip height inspite of the change in ankle angle. These results are striking evidenceof the complex effects of acquiring an ostensibly simple skill. Theirfurther study may illuminate the etiology and functional impact of thecomplex plasticity associated with new skills, and may guide developmentof new methods to improve function after trauma or disease.

Example 2 Operant Conditioning of a Spinal Reflex can Improve Locomotionafter Spinal Cord Injury in Humans Overview

Operant conditioning protocols can modify the activity of specificspinal cord pathways and can thereby affect behaviors that use thesepathways. To explore the therapeutic application of these protocols, westudied the impact of down-conditioning the soleus H-reflex in peoplewith impaired locomotion caused by chronic incomplete spinal cordinjury. After a baseline period in which soleus H-reflex size wasmeasured and locomotion was assessed, subjects completed either 30H-reflex down-conditioning sessions (DC subjects) or 30 sessions inwhich the H-reflex was simply measured (Unconditioned (UC) subjects),and locomotion was reassessed. Over the 30 sessions, the soleus H-reflexdecreased in two-thirds of the DC subjects (a success rate similar tothat in normal subjects) and remained smaller several months later. Inthese subjects, locomotion became faster and more symmetrical, and themodulation of EMG activity across the step-cycle increased bilaterally.Furthermore, beginning about halfway through the conditioning sessions,all of these subjects commented spontaneously that they were walkingfaster and farther in their daily lives, and several noted less clonus,easier stepping, less arm weight-bearing, and/or other improvements. TheH-reflex did not decrease in the other DC subjects or in any of the UCsubjects; and their locomotion did not improve. These results suggestthat reflex conditioning protocols can enhance recovery of functionafter incomplete spinal cord injuries and possibly in other disorders aswell. Because they are able to target specific spinal pathways, theseprotocols could be designed to address each individual's particulardeficits, and might thereby complement other rehabilitation methods.

The present study is the first effort to use spinal reflex conditioningto improve function in people with SCI. It focuses on people in whom achronic incomplete SCI has produced a spastic gait disordercharacterized by hyperreflexia and abnormal reflex modulation in ankleextensor muscles (Dietz and Sinkjaer, 2007; Nielsen et al., 2007). Bydown-conditioning the soleus H-reflex, the study sought to reduce theseabnormalities, and to thereby improve the speed and symmetry oflocomotion. The results are clear and encouraging. They suggest thatoperant conditioning protocols could provide a valuable new approach torestoring useful function after spinal cord injuries or in otherneuromuscular disorders.

Materials and Methods Subjects

The study participants were 13 ambulatory subjects (9 men and 4 women,ages 28-68 yrs, mean age 48.4(±13.9 SD)) (Table 2) who had suffered aspinal cord injury (SCI) 8 months to 50 years earlier that had impairedlocomotion. All subjects gave informed consent for the study, which wasreviewed and approved by the Institutional Review Board of Helen HayesHospital. A physiatrist (F.P.) determined each prospective subject'seligibility for the study. The inclusion criteria were: (1) a stableSCI-related motor deficit (>6 months after lesion); (2) ability toambulate at least 10 m either with or without an assistive device (e.g.,cane, crutches, or walker); (3) signs of spasticity (i.e., exaggeratedH-reflexes, increased muscle tone, score ≧1 on Modified Ashworth scale)and weak ankle dorsiflexion (i.e., manual dorsiflexor muscle strength atankle <5) unilaterally or bilaterally; (4) a reasonable expectation thatcurrent medications would not change over the period of the study (e.g.,an anti-spasticity medication such as baclofen, diazepam, ordantrolene); and (5) medical clearance to participate. The exclusioncriteria were: (1) a lower motoneuron injury; (2) a known cardiaccondition; (3) another medically unstable condition; (4) cognitiveimpairment; and/or (5) daily use of functional electrical stimulation tocounteract foot drop. In the subjects who exhibited bilateral motorimpairments, the soleus H-reflex of the more impaired leg was studied.

The subjects were randomly assigned (at a 2/1 ratio) to theDown-conditioning (DC) group (6 men and 3 women; ages 30-68 yrs, mean48.2(±14.0 SD) yrs; Subjects 1-9 in Table 2) or the Unconditioned (UC)group (3 men and 1 woman; ages 28-67 yrs, mean 48.8(±15.7) yrs);Subjects 10-13 in Table 2). The primary purpose of the UC group was toestablish that H-reflex decrease was specific to the down-conditioningprotocol.

TABLE 2 Profiles of Conditioning (DC) and Unconditioned (UC) Subjects.Group Age Gender Cause SCI Level AIS Yrs Post SCI DC 61 M NT C7 D 10 ″68 M T C3 D 2.5 ″ 37 M T T6 D 0.7 ″ 39 M T T11 D 1 ″ 30 F T C5 D 7 ″ 34M T C2 C 1.5 ″ 51 M T C5 D 0.8 ″ 65 F NT T4 D 49 ″ 48 F NT T7 D 5 UC 53M T C5 D 3 ″ 28 M T C7 C 5.5 ″ 67 F NT T4 D 50 ″ 48 M T C3 D 0.8 M,Male; F, female; T, trauma; NT, non-trauma; SCI level, the highestspinal cord level that was damaged; AIS, American Spinal InjuryAssociation Impairment Scale;, Cause: cause of spinal cord damage (T:trauma, NT: non-trauma).

Operant Conditioning of the Soleus H-Reflex Overview

The operant conditioning protocol for the human soleus H-reflex wasoriginally developed in a study of neurologically normal subjects and isdescribed in detail in Thompson et al. (2009). It is summarized here,with several minor modifications noted.

FIGS. 11A-11C summarize the protocol. After 1-3 preliminary sessions inwhich appropriate background EMG and M-wave criteria were defined, eachsubject completed 6 Baseline sessions and 30 Control (UC subjects) orConditioning (DC subjects) sessions at a rate of 3 per week. Eachsession lasted about one hour and occurred within the same 2-h timewindow (to prevent the normal diurnal variation in reflex size fromaffecting the results (Wolpaw and Seegal, 1982; Chen and Wolpaw, 1994;Carp et al., 2006b; Lagerquist et al., 2006)). As FIG. 11B shows, in the6 Baseline sessions of all subjects, and in the 30 Control and 2Follow-up sessions of the UC subjects, 225 Control H-reflexes (in three75-trial blocks) were elicited during standing. In these 225 Controltrials there was no feedback to the subject regarding H-reflex size. Incontrast, in the 30 Conditioning and 2 Follow-up sessions of the DCsubjects, 20 Control H-reflexes were elicited, and then 225 ConditionedH-reflexes (in three 75-trial blocks) were elicited. In these 225Conditioning trials, the subject was asked to decrease the H-reflex andwas given immediate visual feedback after each stimulus (see below) toindicate whether the resulting H-reflex was smaller than a criterionvalue. Background EMG and M-wave size were kept stable throughout datacollection.

Electrical Stimulation and EMG Recording

At the beginning of each session, EMG recording and stimulatingelectrodes were placed over the leg. EMG activity from soleus and itsantagonist tibialis anterior (TA) was recorded with surfaceself-adhesive Ag—AgCl electrodes (2.2×3.5 cm, Vermed), amplified,band-pass filtered (10-1000 Hz), digitized (5,000 Hz), and stored. Toelicit the H-reflex, the tibial nerve was stimulated in the poplitealfossa, using surface Ag—AgCl electrodes (2.2×2.2 cm for the cathode and2.2×3.5 cm for the anode; Vermed) and a Grass S88 stimulator (with aCCUl constant current unit and an SIU5 stimulus isolation unit;Astro-Med). The stimulating electrode pair was placed so as to minimizethe H-reflex threshold and to avoid stimulating other nerves. Thisplacement was accomplished by monitoring the EMG of soleus and TA andpalpating other lower-leg muscles, such as the peroneal muscle group. Toavoid session-to-session variability in electrode placement, theirpositions were mapped in relation to landmarks on the skin (e.g., scarsor moles). The same individuals (AKT and BMA) placed the electrodes andconducted every session for every subject.

The soleus H-reflex was elicited by a 1-ms square stimulus pulse whilethe subject maintained a natural standing posture with hands resting ona horizontal bar at waist height and with stable levels of soleus and TAbackground EMG activity. The stimulus occurred after the subject hadmaintained rectified soleus and TA EMG activity within specified rangesfor at least 2 s. Typically, the soleus range was 10-20% of a maximumvoluntary contraction, and the TA range was 0-7 μV (i.e., restinglevel). The minimum inter-stimulus interval was 5 s.

Session Protocol

At the beginning of each session, an H-reflex/M-wave (H-M) recruitmentcurve was obtained. All H-reflex and M-wave measurements were inabsolute value (i.e., equivalent to rectified EMG). Stimulus intensitywas varied in increments of 1.25-2.50 mA from below soleus H-reflexthreshold, to the maximum H-reflex (H_(max)), to an intensity just abovethat needed to elicit the maximum M-wave (M_(max)) (Kido et al., 2004b;Makihara et al., 2012). About 10 different intensities were used toobtain each recruitment curve. At each intensity, four EMG responseswere averaged to measure the H-reflex and M-wave. The stimulus amplitudeused for the subsequent H-reflex trials fell on the rising phase of theH-reflex recruitment curve and typically produced an M-wave just abovethreshold. In each subject, this M-wave size was maintained for theH-reflex trials of all the sessions.

In the Baseline and Control sessions (i.e., FIG. 11B), the H-Mrecruitment curve was followed by three 75-trial blocks of Controltrials, in which the subject was not asked to change the H-reflex andwas not given visual feedback as to H-reflex size (see Visual Feedback).In the Conditioning sessions (i.e., FIG. 11B), the H-M recruitment curvewas followed by a 20-trial block of Control trials identical to those ofthe Baseline or Control sessions; and this block was followed by three75-trial blocks of Conditioning trials, in which the subject was askedto decrease H-reflex size and was provided with immediate visualfeedback that indicated his or her success in doing so (see below).

Visual Feedback

The visual feedback screens for Control and Conditioning trials havebeen described in detail previously (Thompson et al., 2009) and areillustrated in FIG. 11C. Briefly, the screen could present two graphs,one for soleus background EMG activity and one for H-reflex size. InControl trials, only the background EMG graph was shown: if the subjectkept the height of the vertical bar (i.e., soleus background EMGactivity level (in absolute value)) in the specified range for 2 s, andat least 5 s had passed since the last stimulus, a stimulus pulseelicited the H-reflex and M-wave. In Conditioning trials, the backgroundEMG graph was shown and, in addition, the H-reflex size graph was shown.This graph constantly showed a heavy horizontal line indicating thesubject's average H-reflex size for the 6 Baseline Sessions and a shadedarea that indicated the H-reflex size range that satisfied the currentdown-conditioning criterion value. Two hundred msec after the stimulus,a vertical bar reflecting H-reflex size appeared. The bar was green(indicating success) when the H-reflex fell within the shaded area(i.e., was below the criterion value), and the bar was red (indicatingfailure) when the H-reflex size was not below the criterion value. Inaddition, the current success rate (i.e., the percent of the trials ofthe current 75-trial block that were successful) was shown below thegraph and was updated after each trial. Thus, for each Control trial,the visual feedback simply helped the subject maintain the requiredpre-stimulus background EMG activity. In contrast, for each Conditioningtrial, the visual feedback also informed the subject as to whether s/hehad succeeded in producing an H-reflex small enough to satisfy the sizecriterion, and it showed the success rate for the current block oftrials.

In each Conditioning session, the criterion value for the first block of75 Conditioning trials was based on the immediately preceding block of20 Control trials, and the criterion values for the second and thirdblocks of Conditioning trials were based on the H-reflexes of theimmediately preceding block of 75 Conditioning trials. The criterion wasselected so that if H-reflex values for the new block were similar tothose for the previous block, 50-60% of the trials would be successful(Chen and Wolpaw, 1995). For each block, the subject earned a modestextra monetary reward when the success rate exceeded 50%. (See (Thompsonet al., 2009) for full details.)

Analysis of Conditioned and Control H-Reflexes

For each session of each subject, we determined the average H-reflexsize for the 225 trials of the three 75-trial blocks (FIG. 11B). Thisvalue is called the Conditioned H-reflex size (regardless of whether thesession is from a Conditioning (DC) subject or an Unconditioned (UC)subject). In addition, for each session of each subject, we determinedthe average H-reflex size for 20 Control trials. This value is calledthe Control H-reflex size. For the 6 Baseline sessions of all subjectsand the 30 Control sessions of the UC subjects, these 20 Control trialswere the first 20 trials of the first 75-trial block. For the 30Conditioning sessions and the Follow-up sessions of the DC subjects,these 20 Control trials were elicited prior to the three 75-trial blocksof Conditioning trials, as indicated in FIG. 11B. H-reflex size wasdefined as average absolute value of soleus EMG (i.e., equivalent torectified EMG) in the H-reflex window (typically 30-45 ms after thestimulus) minus average absolute value of soleus background EMG.

To determine for each subject whether the Conditioned H-reflex sizechanged significantly over the 30 Conditioning or Control sessions, theaverage H-reflexes for the 225 trials of the three 75-trial blocks ofthe final 6 sessions (i.e., sessions 25-30) were compared to the averageH-reflexes for the 225 trials of the three 75-trial blocks of the 6baseline sessions by unpaired t test (two-tailed). To determine for eachsubject the final Conditioned H-reflex size, the average H-reflexes forthe 225 trials of the three 75-trial blocks of the final 3 sessions(i.e., sessions 28-30) were averaged, and the result was expressed inpercentage of the average H-reflex for the 225 trials of the three75-trial blocks of the 6 Baseline sessions. (Thus, a value of 100%indicated no change.) To determine for each subject the final ControlH-reflex size, the average H-reflexes for the 20 Control trials ofsessions 28-30 were averaged, and the result was expressed in percentageof the average H-reflex for the 20 Control trials of the 6 Baselinesessions.

To assess the stability of soleus M_(max), soleus M-wave size in Controland Conditioning trials, and soleus and tibialis anterior (TA)background EMG levels, a repeated measures ANOVA was applied to the meanvalues across successive 6-session blocks beginning with the 6 Baselinesessions. Soleus M_(max), soleus M-wave size during H-reflexelicitation, and soleus and TA background EMG levels remained stableacross all the sessions in both the Conditioning (DC) and Unconditioned(UC) groups (p>0.33 for all of these measures in both groups, one-wayrepeated measures ANOVA). These results confirmed the stability of EMGrecording and nerve stimulation conditions in this study, and thussupported the validity of the methodology.

Assessment of Locomotion

Locomotion was assessed before and after the 30 Conditioning or Controlsessions. These assessments occurred on non-session days. First, thesubject was asked to walk 10 m overground at a comfortable speed threetimes, and the average walking time was determined.

Then, locomotor symmetry, EMG activity, and H-reflex modulation weremeasured. For these measurements during locomotion, any subject who worean ankle foot orthosis was asked to remove it. Surface EMG was recordedfrom the soleus, TA, vastus lateralis (VL), and biceps femoris (BF)muscles of both legs. Footswitch cells inserted between the subject'sshoe and foot detected foot contact (typically, heel or toe contact).For locomotor H-reflex measurement, single 1-ms square-pulse stimuliwere delivered at different points in the step cycle to evaluatephase-dependent H-reflex modulation (Capaday and Stein, 1986; Stein andCapaday, 1988; Ethier et al., 2003; Kido et al., 2004b). The stimulusinterval was set to be long enough to have at least one fullunstimulated step cycle between successive stimuli.

Those subjects who were able to walk on a treadmill for several minuteswith a consistent stepping rhythm did so twice at a comfortable speed:once without H-reflex elicitation and once while tibial nervestimulation elicited the soleus H-reflex. Subjects who were not able towalk on the treadmill repeated 10-m overground walking withoutstimulation until at least 50 steps were obtained. They then repeated10-m overground walking with H-reflex elicitation until at least 50stimulated steps were obtained. During these measurements, the subjectstook sitting breaks as often as needed. The data were assessed asdescribed below, and the locomotor measurements obtained before andafter the 30 Conditioning or Control sessions were compared.

For analysis of locomotor EMG activity, the complete step cycle wasdivided into 12 bins of equal duration (Kido et al., 2004a; Makihara etal., 2012). For the muscles of the conditioned leg, the step cycle wentfrom the conditioned leg's foot contact (cFC) to the next cFC; for themuscles of the contralateral (i.e., nonconditioned) leg, the step cyclewent from the nonconditioned leg's foot contact (nFC) to the next nFC.For each muscle of each subject, the average rectified EMG amplitude ineach of the 12 bins was determined and expressed in percent of theamplitude in the bin with the highest amplitude. The degree to whicheach muscle's activity was modulated during locomotion was determined bycalculating its Modulation Index (MI) in percent as: 100×[(highest binamplitude−lowest bin amplitude)/highest bin amplitude] (Zehr and Kido,2001; Zehr and Loadman, 2012). Thus, an MI of 0% indicated that a muscledid not modulate its activity at all over the step cycle.

To assess gait quality, we examined step-cycle symmetry (i.e., the ratioof the time between the nonconditioned leg's foot contact (nFC) and theconditioned leg's foot contact (cFC) to the time between cFC and nFC). Aratio of 1 indicates a symmetrical gait.

Spontaneous Subject Comments

Over the three months of the study, the subjects were not asked aboutthe current state of their motor function or whether their disabilitieshad changed in any way. Nevertheless, many volunteered comments whenthey came in for sessions. We kept a record of these spontaneouscomments and when they were first made. They fall into distinctcategories and tell a clear story both in their nature and in theirtiming. Thus, they are presented as a unique and important component ofthe results.

Results

All 13 subjects completed the 6 Baseline sessions and 30 Conditioning orControl sessions. In each subject, soleus M., soleus M-wave size inControl and Conditioning trials, and soleus and tibialis anterior (TA)background EMG levels remained stable across all the sessions. The DCand UC groups did not differ significantly in soleus and TA backgroundEMG levels (p=0.90 and 0.81 by two-way repeated measures ANOVA,respectively), M-wave sizes (p=0.71), or Baseline H-reflex sizes(p=0.11).

The results comprise three categories of data: Conditioned and ControlH-reflex sizes over the course of the sessions; locomotor speed,symmetry, EMG activity, and H-reflex modulation before and after the 30Conditioning or Control sessions; and the spontaneous comments of thesubjects over the course of the sessions. These three data sets aredescribed here.

H-Reflex Size

FIG. 12A shows the final Conditioned H-reflex sizes of the DC subjects,the UC subjects, and, for comparison, the normal DC subjects of Thompsonet al. (2009). The filled triangles represent the DC subjects in whomdown-conditioning was successful (i.e., the average ConditionedH-reflexes for Conditioning sessions 25-30 were significantly less thanthose for the 6 Baseline sessions). In the other DC subjects (opentriangles), the H-reflex did not change significantly. The success ratefor the subjects with SCI (i.e., 6/9 or 67%) is slightly, but notsignificantly, less than that for neurologically normal subjects (i.e.,8/9 or 89%) (Thompson et al., 2009) or for normal monkeys, rats, andmice (i.e., 75-80%) (Wolpaw et al., 1983; Wolpaw, 1987; Chen and Wolpaw,1995; Carp et al., 2006a). In contrast, the Conditioned H-reflex did notdecrease significantly in any of the UC subjects; and the DC and UCgroups differed significantly in final H-reflex size (p=0.025 byunpaired t test). Thus, H-reflex decrease was specific to the DC group.Indeed, it should be noted that the UC group as a whole showed a slightbut significant increase in the Conditioned H-reflex (to 116(±7 SE) % ofbaseline; p=0.05 by paired t test). This may have been a nonspecificeffect of continued exposure over 30 sessions to the baseline protocolof standing, providing soleus background EMG, and having the H-reflexelicited.

As noted in our previous study of H-reflex conditioning in normalsubjects (Thompson et al., 2009), successful DC subjects reported that,in the first 4-5 Conditioning sessions, they tried different strategiesfor decreasing the H-reflex, identified an effective strategy, and thenused it in subsequent Conditioning trials. Their reported techniqueswere comparable to those of normal subjects (Table 2 of Thompson et al.,2009) (e.g., meditation, anticipating stimulus occurrence).

FIGS. 12B and 12C show H-reflexes from a successful DC subject duringthe Baseline period (solid) and at the end of the 30 Conditioningsessions (dashed). FIG. 12B illustrates the change in the ConditionedH-reflex (i.e., the H-reflex for the three 75-trial blocks in which thesubject was asked to decrease the H-reflex and was provided withimmediate feedback as to whether the reflex satisfied the sizecriterion). FIG. 12C illustrates the change in the Control H-reflex(i.e., the H-reflex for the first 20 trials of each Conditioning sessionin which the subject was not asked to decrease the H-reflex and was notprovided with feedback as to reflex size). Both the Conditioned andControl H-reflexes are smaller after down-conditioning. Backgroundsoleus EMG level and M-wave size do not change.

FIGS. 13A-13F show the average courses of H-reflex changes for subjectswith SCI (FIGS. 13A-13C; from this study) and for normal subjects (FIGS.13D-13F; from Thompson et al. 2009) in whom down-conditioning wassuccessful. FIGS. 13A and 13D show the Conditioned H-reflex change.FIGS. 13B and 13E show the Control H-reflex change. Finally, FIGS. 13Cand 13F show the change in the within-session difference between theConditioned and Control H-reflexes. This difference representstask-dependent adaptation; that is, the decrease that the subjects wereable to produce immediately when they were asked to decrease theH-reflex.

These courses of change are noteworthy in several respects. First, thefinal average value of the Conditioned H-reflex (i.e., the average ofthe last 3 Conditioning sessions) in the subjects with SCI is identicalto that in normal subjects (i.e., 69(±11 SE) % and 69(±6) % of Baseline,respectively). Second, the final value of the Control H-reflex in thesubjects with SCI is significantly smaller than in normal subjects(i.e., 76(±9) % of baseline vs. 84(±6) %, respectively (p=0.01,two-tailed t test)). Thus, the subjects with SCI decreased the ControlH-reflex more than normal subjects. Third, like normal subjects, thesubjects with SCI display an appropriate task-dependent adaptation(i.e., a session's average Conditioned H-reflex is smaller than itsaverage Control H-reflex) that begins after four Conditioning sessionsand remains about the same thenceforth. However, this task-dependentadaptation is significantly less in the subjects with SCI than in normalsubjects (i.e., averages of −7(±3) % and −15(±6) %, respectively(p=0.01, two-tailed t test)). The greater decrease in the ControlH-reflex in the subjects with SCI combines with their lessertask-dependent adaptation to yield a decrease in the ConditionedH-reflex that is identical to that found in normal subjects.

Four of the successful DC subjects completed Follow-up sessions onemonth and 3 months after the Conditioning sessions ended. At both onemonth and 3 months, the Conditioned H-reflex remained reduced in everysubject, averaging 65(±10 SE) % and 58(±10) % of baseline value,respectively. One DC subject also completed a 6-month Follow-up session.The Conditioned H-reflex was 26% of baseline, comparable to the value of18% for the final three Conditioning sessions.

In the successful DC subjects, the H_(max) measured at the beginning ofeach session also decreased with down-conditioning, paralleling thechanges in the Control H-reflex (final value 84(±5 SE) % of baseline,p<0.001, paired t test). In contrast, H. did not change significantly inthe 7 subjects in whom the H-reflex did not decrease.

Locomotor Speed, Symmetry, EMG Activity, and H-Reflex Modulation WalkingSpeed

Over the 30 Conditioning or Control sessions, the subjects' 10-m walkingspeeds increased by 0-123%. The increase was substantial and significantin the 6 DC subjects in whom the H-reflex decreased (+59(±19 SE) %;p=0.03, paired t test). Furthermore, the two subjects who increasedtheir walking speeds most also decreased their dependence on anassistive device in their daily lives: one switched from a walker tocrutches and the other switched from a walker to a cane. In contrast, inthe 7 subjects in whom the H-reflex did not decrease, walking speedincreased less and not significantly (+25(±13) %; p=0.10). In none ofthese subjects did dependence on an assistive device change. FIG. 4Asummarizes these results.

Locomotor Symmetry

To assess gait quality, we examined step-cycle symmetry (i.e., the ratioof the time between the nonconditioned leg's foot contact (nFC) and theconditioned leg's foot contact (cFC) to the time between cFC and nFC). Aratio of 1 indicates a symmetrical gait. During the Baseline period, theratio was always >1 because foot drop and/or spasticity prolonged theswing phase of the conditioned leg (which was the more impaired leg)and/or because spasticity and the resulting instability in theconditioned leg shortened its stance (i.e., weight-bearing) phase. Afterthe 30 Conditioning or Control sessions, this ratio decreased in everysubject in whom the H-reflex decreased, becoming closer to 1 (p=0.05,paired t test). In contrast, the ratio increased in every subject inwhom the H-reflex did not decrease (p=0.02). FIG. 14B summarizes theseresults. Thus, the successful DC subjects walked faster and moresymmetrically; while the subjects in whom the H-reflex did not decreasewalked slightly but not significantly faster and walked lesssymmetrically.

FIG. 14C shows the nFC-cFC and cFC-nFC time intervals in one DC subjectbefore and after successful conditioning. Before conditioning, thenFC-cFC time interval was longer than the cFC-nFC interval. Afterconditioning, the two intervals were equal, indicating that locomotionhad become more symmetrical.

Locomotor EMG Activity

To further assess changes in walking, locomotor EMG activity wasrecorded from the soleus, TA, vastus lateralis (VL), and biceps femoris(BF) muscles of both legs before and after the 30 Conditioning orControl sessions, and each muscle's Modulation Index (MI) was determinedas described in the Methods.

MI values varied widely across subjects and across the 8 muscles of eachsubject, with many abnormally low values (i.e., >2 SD below the averagefor 12 normal subjects (Unpub. data)). In the DC subjects in whom theH-reflex decreased, the average MI rose significantly (from 74(±175 D) %to 80(±11) %) (p=0.005, paired t test). This improvement was bilateral;it was not limited to the muscles of the conditioned leg. Thus,successful H-reflex down-conditioning was associated with significantincrease in the degree to which ankle and knee flexor and extensormuscles of both legs modulated their activity in synchrony with the stepcycle. In the 7 subjects in whom the H-reflex did not decrease, theaverage MI did not change (84(±8) % before and 84(±10) % after)(p=0.25). (Although the average initial MI was higher in this group, itwas still below normal (i.e., 89% (Unpub. data)). Thus, this lack ofincrease cannot be attributed simply to a ceiling effect.)

FIG. 15 shows modulation over the step cycle in the muscles of both legsfor one DC subject before and after successful down-conditioning. Afterconditioning, soleus activity is increased and TA activity is decreasedduring mid-to-late stance in both legs. These bilateral improvements inthe modulation of muscle activity controlling movement about the anklejoint probably resulted in more effective weight-bearing and push-off,and thereby contributed to this subject's increased walking speed (from0.59 m/s to 0.80 m/s). Locomotor EMG modulation also increased in othermuscles.

H-Reflex Modulation During Locomotion

In addition to recording EMG activity during undisturbed locomotion, wealso elicited soleus H-reflexes during locomotion. As described abovefor locomotor EMG analysis, the step cycle was divided into 12 bins ofequal duration and average H-reflex size for each bin was determined.The average of these 12 values defined the average locomotor H-reflex.

In the successful DC subjects, the average locomotor H-reflex alsodecreased (to 59(±17 SE) % of baseline value; p=0.04 by paired t test).Thus, in humans as in rats (Chen et al., 2005; Chen et al., 2006b), anH-reflex decrease produced by the conditioning protocol was also evidentduring locomotion. The decreased average locomotor H-reflex reflectedthe combination of an overall decrease throughout the step cycle and adecrease concentrated in the swing phase, the period when the locomotorH-reflex is small in normal subjects. In contrast, in the subjects inwhom the H-reflex did not decrease, the average locomotor H-reflexshowed an insignificant increase (to 125(±17) % of baseline value,p=0.15).

FIG. 16 illustrates the decrease in the locomotor H-reflex of onesuccessful DC subject. It is markedly reduced throughout the step cycle.In addition, its modulation across the step cycle has become morenormal: the reflex is smallest during the swing phase. Locomotor soleusEMG has also become more normal, with much less inappropriate activityduring the swing phase.

Spontaneous Subject Comments

Although subjects were not questioned about the current state of theirdisabilities during the study, many volunteered spontaneous comments.The 13 subjects made a total of 30 positive comments of 10 differentkinds and no negative comments.

FIG. 17 lists these 10 different kinds of positive comments andindicates when during the study they were first made by the DC subjectsin whom the H-reflex decreased significantly and by the subjects in whomthe H-reflex did not decrease. The contrast is striking: 25 of the 30positive comments were made by the 6 DC subjects in whomdown-conditioning was successful and only 5 by the other 7 subjects(p=0.0027, Mann-Whitney U test). All 6 successful DC subjects reportedwalking faster and farther, and 1-3 of them made each of the other 8positive comments. Furthermore, and most importantly, these comments didnot occur until decrease in the Conditioned H-reflex was substantial anddecrease in the Control reflex had begun (i.e., the 12^(th) conditioningsession and later; FIG. 13).

These spontaneous comments are consistent with the quantitative datashowing that successful H-reflex down-conditioning was associated withfaster walking, more symmetrical walking, better locomotor EMGmodulation, and decreased locomotor H-reflexes. By showing that theseobjective effects were apparent to the subjects in their daily lives,the comments indicate that successful H-reflex conditioning hadsubstantial practical impact.

Discussion

This study asked two questions. First, can people with chronic SCI andimpaired locomotion decrease the soleus H-reflex in response to anoperant conditioning protocol? Second, if so, is H-reflex decreaseassociated with improved locomotion? The results answer these questionsclearly. First, people with incomplete SCI and impaired locomotiondecreased the H-reflex in response to an operant down-conditioningprotocol (DC subjects). Their success rate and magnitude of reflexchange were comparable to those of people who were neurologicallynormal. H-reflex decrease was specific to the down-conditioningprotocol; it did not occur in subjects in whom the H-reflex was simplyelicited without feedback (UC subjects).

Second, H-reflex decrease was associated with faster and moresymmetrical locomotion. The improvement was evident both in quantitativetesting and, most important, to the subjects themselves in their dailylives. It did not occur in people in whom the H-reflex did not decrease,whether they were UC subjects or unsuccessful DC subjects. Indeed,locomotion became less symmetrical in every subject in whom the H-reflexdid not decrease. (This greater asymmetry, combined with their slightincrease in walking speed, suggests that these subjects expected to bewalking faster after the 30 sessions, and thus walked slightly faster bytaking more asymmetrical steps.)

These results indicate that reflex conditioning protocols might help torestore motor function after SCI or in other disorders. They alsoprovide insight into the factors shaping the plasticity associated withH-reflex conditioning and into its potential therapeutic applications.

H-Reflex Conditioning in People with or without Spinal Cord Injury

The subjects with SCI were not significantly different fromneurologically normal subjects (Thompson et al., 2009) in theprobability of successful down-conditioning, and they were identical inthe average magnitude of their H-reflex decrease (i.e., 31%). Thisfinding is consistent with results for soleus H-reflex conditioning inspinal cord-injured rats (Chen et al., 2006b) and biceps spinal stretchreflex conditioning in people with SCI (Segal and Wolf, 1994).

The subjects with SCI did differ significantly from normal subjects inthe composition of their final H-reflex change. Conditioned H-reflexchange is composed of task-dependent adaptation (i.e., within-sessiondifference between the Control H-reflex and the Conditioned H-reflex)plus long-term change (i.e., across-session change in the ControlH-reflex) (Thompson et al., 2009). The former is thought to reflectimmediate change in cortical influence (e.g., on presynaptic inhibition)while the latter reflects spinal cord plasticity. Task-dependentadaptation was significantly less in subjects with SCI than inneurologically normal subjects (−7% vs. −15%), while long-term changewas significantly more (−24% vs. −16%). The lesser task-dependentadaptation in subjects with SCI may reflect damage to the corticospinaltract (CST), the spinal cord pathway principally responsible forH-reflex conditioning (Chen et al., 1996, 1999; Chen et al., 2002; Chenand Wolpaw, 2002), and may account for the slightly slower course ofH-reflex decrease (i.e., over 30 sessions versus 24 in normal subjects(Thompson et al., 2009)).

The greater long-term change in subjects with SCI is more surprising. Itmay result from the fact that task-dependent adaptation affects theH-reflex pathway only during the conditioning protocol, while long-termchange affects it continuously, and thus has much wider effects. Becausethe spinal cord serves many behaviors, spinal cord plasticity affectsmany behaviors. In neurologically normal subjects, the spinal cordplasticity responsible for the long-term change in the H-reflex islikely to disturb behaviors such as locomotion, which are alreadysatisfactory; and it may thereby lead to additional plasticity thatcompensates for the change in the H-reflex pathway. Animal data supportthis inference. In normal rats, up- or down-conditioning of the soleusH-reflex increases or decreases, respectively, the soleus locomotorburst, but does not disturb the symmetry of the step cycle, suggestingthat plasticity elsewhere preserves this symmetry (Chen et al., 2005).Indeed, in normal rats a conditioned change in the soleus H-reflex isusually accompanied by an opposite change in the quadriceps H-reflex,and also by changes in ankle and hip joint angles during locomotion(Chen et al., 2011). The angle changes are reciprocal, and help toensure that hip height during stance does not change. It appears that innormal rats, and presumably in normal humans as well, compensatoryplasticity prevents the plasticity responsible for the modified H-reflexfrom disrupting normal locomotion.

Furthermore, in normal subjects, the processes that preserve otherbehaviors may reduce the long-term plasticity that decreases theH-reflex. Wolpaw (2010) hypothesizes that spinal neurons and pathwaysare maintained in a state of “negotiated equilibrium,” a balance thatensures the satisfactory performance of all the behaviors in theindividual's current repertoire (Nielsen et al., 1993; Ozmerdivenli etal., 2002; Zehr, 2006). In normal subjects, the spinal cord plasticityunderlying the new behavior (i.e., a smaller H-reflex) requires thecreation of a new equilibrium that produces a smaller H-reflex and stillcontinues to serve other behaviors satisfactorily. This new negotiationproduces concurrent adaptive changes in the networks supporting themultiple behaviors that use the pathway. For behaviors such aslocomotion, which are already satisfactory, these adaptations are likelyto impede the long-term plasticity that decreases the H-reflex. Theresult is that, in normal subjects, much of the final change in theconditioned H-reflex is due to task-dependent adaptation, which does notdisturb other behaviors.

In contrast, for subjects with SCI, the spinal cord plasticityresponsible for the long-term H-reflex decrease improves locomotion, animportant motor skill. Similarly, in rats in which a spinal cord injuryhas produced an asymmetrical step cycle, appropriate conditioning of thesoleus H-reflex restores step-cycle symmetry (Chen et al., 2006b). Inthese SCI rats, as in the subjects of this study, the long-term changein the H-reflex is doubly adaptive: it increases reward probability inthe conditioning protocol and it also improves locomotion. It creates anew spinal cord equilibrium superior to the one that prevailed beforeH-reflex conditioning. In sum, it is probable that long-term H-reflexchange is greater in subjects with SCI than in normal subjects becauseit serves more than the new behavior, it also benefits locomotion.

Potential Therapeutic Applications of Reflex Conditioning Protocols

This study sought to down-condition the soleus H-reflex on the rationalethat reducing the activity of this pathway would reduce thehyperreflexia that impaired locomotion in these subjects with incompleteSCI (Dietz and Sinkjaer, 2007; Nielsen et al., 2007). Successfuldown-conditioning did improve locomotion. Walking became faster and moresymmetrical. Furthermore, the locomotor behaviors of knee and ankleextensor and flexor muscles in both legs became more strongly modulatedin synchrony with the step cycle, which presumably contributed to theimprovement in walking speed and symmetry.

These encouraging results are surprising in their breadth. It isunlikely that the plasticity underlying a smaller soleus H-reflex in oneleg could itself have such broad beneficial effects on walking,including increasing the locomotor EMG modulation of contralateralmuscles. This broad impact, combined with the animal data discussedabove, implies that in these subjects with SCI, H-reflex conditioningtriggered additional plasticity in other pathways important inlocomotion, and thereby changed the entire behavior. These subjects hadbeen injured 0.7-10 years earlier; and their locomotor deficits werestable. In this setting, the acquisition of a new behavior, adown-conditioned soleus H-reflex, disturbed the post-injury equilibriumthat the injured spinal cord had reached. It apparently triggeredwidespread adaptive plasticity that produced a new equilibrium that bothdecreased the H-reflex and improved locomotion.

Because they can target particular spinal pathways and can either weakenor strengthen the activity of these pathways, reflex conditioningprotocols can be designed to focus on each individual's particulardeficits. The present study down-conditioned the soleus H-reflex becauselocomotion was impaired by hyperreflexia. In contrast, the Chen et al.(Chen et al., 2006b) study in spinal cord-injured rats up-conditionedthe soleus H-reflex because locomotion was impaired by weak rightstance. In both cases, the intervention was effective. This flexibilityand specificity are distinctive and desirable features of this newtherapeutic approach; and they distinguish it from less focusedinterventions such as botulinum toxin or baclofen, which simply weakenmuscles or reflexes and may have undesirable side effects (Dario et al.,2004; Dario and Tomei, 2004; Sheean, 2006; Ward, 2008; Thomas andSimpson, 2012).

Reflex conditioning protocols might supplement therapies that involverepetition of complex behaviors (e.g., body-weight supported treadmilltraining (Edgerton et al., 2008), constraint-induced movement therapy(Taub and Uswatte, 2003; Wolf et al., 2006)). Indeed, H-reflexconditioning might be combined with treadmill locomotion so thatsubjects are rewarded for changing the reflex in a specific phase oflocomotion. This combination might help restore normal reflex modulationacross the step cycle (Stein and Capaday, 1988). The results of thepresent study also encourage therapeutic exploration of other reflexconditioning protocols. For example, in rats, reciprocal inhibition ofsoleus by common peroneal nerve stimulation can be increased ordecreased by operant conditioning (Chen et al., 2006a).

Certainly, the dependence of reflex conditioning on the CST will affectits efficacy in people with SCI. On the American Spinal InjuryAssociation Impairment Scale (AIS), the disabilities of the presentsubjects were rated C or D. Although their success rate was notsignificantly different from that of normal subjects (Thompson et al.,2009), it was lower; and the extent to which reflex conditioning ispossible in people with more severe impairments is unclear. While futureimprovements in the conditioning protocol may increase success, the needfor supraspinal input will remain. On the other hand, reflexconditioning may also prove useful for disorders in which the CST is notaffected. For example, in rats in which peripheral nerve transection andreinnervation have produced disordered afferent connections, H-reflexup-conditioning can help to restore more normal reflex function (Englishet al., 2007).

Conclusions

In people with impaired locomotion due to chronic spinal cord injury,down-conditioning of the soleus H-reflex in the more impaired leg wasassociated with faster and more symmetrical locomotion. This improvementwas apparent to the subjects in their daily lives. Similar improvementdid not occur in subjects in whom the H-reflex did not decrease. Spinalreflex conditioning protocols that target each individual's specificdeficits might supplement conventional rehabilitation methods andincrease functional recovery.

Example 3 Preliminary Studies of the Effects of Soleus H-ReflexUp-Conditioning on Locomotion in Rats after Sciatic Nerve Transectionand Repair

In rats in which the sciatic nerve has been transected and repaired, thenerve regenerates, however many peripheral sensory and motor axons donot reach their correct peripheral targets in muscles and sensoryorgans. As a result, locomotion is impaired: stance is weak on theimpaired side and the rat limps. In preliminary studies, we haveexamined the locomotor impact of up-conditioning the soleus (SOL)H-reflex after sciatic transection and repair while regeneration wasoccurring. Rats were implanted with EMG electrodes in right SOL andtibialis anterior (TA) muscles and stimulating cuffs on the rightposterior tibial nerve. After control data collection, the right sciaticnerve was transected and repaired. Beginning 2-10 days later, the ratwas exposed for 120 days to either control-mode (i.e., transected andcontrol-mode (TC rats)) H-reflex data collection, or to SOL H-reflexup-conditioning (i.e., transected and up-conditioning mode (TU rats));and then treadmill locomotion was assessed. To date, the locomotor videodata have been analyzed to determine average hindlimb joint angles andhindlimb length (i.e., distance from hip joint to base of toes) over thecourse of the step-cycle. Right hindlimb length was significantlygreater in the TU rats than in the TN rats. In view of the abnormallyflexed hindlimb position characteristic of sciatic transected/repairedrats, this finding implies that up-conditioning of the soleus H-refleximproved right leg extension during locomotion. We are now planningfurther studies aimed at further verifying this effect and examining theimpact of up-conditioning on the entire behavior of locomotion. Weanticipate that the results will provide new evidence in an anotherdisorder (i.e., nerve injury) that an appropriate operant conditioningprotocol that produces targeted neural plasticity can trigger generalneural plasticity that improves all aspects of a complex CNS functionsuch as locomotion.

Example 4 Preliminary Studies of the Effects of SensorimotorRhythmConditioning on Hand/Arm Function

Voluntary hand/arm movements are normally preceded by decreases in theamplitude of sensorimotor rhythms (i.e., 8-12 Hz mu rhythms and 18-30 Hzbeta rhythms) in the EEG recorded from the scalp over the hand/armregion of contralateral sensorimotor cortex. These decreases are called“event-related desynchronization (ERD).” Sensorimotor rhythms areproduced by thalamocortical/corticothalamic pathways. We are obtainingpreliminary evidence that an operant conditioning protocol thatincreases the ERD prior to movement decreases reaction time and improvesmovement speed and accuracy. If these early results are confirmed, theywill provide evidence that an operant conditioning protocol thatproduces appropriate targeted neural plasticity (TNP) incortical/subcortical pathways can also trigger generalized neuralplasticity (GNP) that improves a complex hand/arm behavior. Protocols ofthis kind could be used to enhance rehabilitation after strokes andother disorders that impair limb functions, and might also be used toimprove limb functions beyond the normal range in people withoutdisabilities.

REFERENCES

Citation of a reference herein shall not be construed as an admissionthat such reference is prior art to the present invention. Allreferences cited herein are hereby incorporated by reference in theirentirety. Certain references are cited by author and date. Below is alisting of various references cited herein, with the references beingidentified by author, date, publication, and page numbers:

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Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

What is claimed is:
 1. A method for restoring or improving nervoussystem function of a subject, said method comprising: providing anoperant conditioning protocol effective to produce targeted neuralplasticity (TNP) in a primary targeted central nervous system (CNS)pathway of a subject; and administering the operant conditioningprotocol to the subject under conditions effective to elicit TNP in theprimary targeted CNS pathway and to elicit generalized neural plasticity(GNP) in one or more other CNS pathways, wherein the elicitation of theGNP in the one or more other CNS pathway serves to restore or improve anervous system function of the subject.
 2. The method according to claim1, wherein the operant conditioning protocol is self-administered by thesubject.
 3. The method according to claim 1, wherein the operantconditioning protocol is designed to down-condition hyperactive reflexesin the subject, up-condition hypoactive reflexes in the subject, and/orup-condition or down-condition other CNS pathways.
 4. The methodaccording to claim 1, wherein the primary targeted CNS pathway isselected from the group consisting of a monosynaptic pathway of a spinalstretch reflex, a monosynaptic pathway of a Hoffman reflex (H-reflex), aspinal pathway of cutaneous reflexes, a corticospinal tract, areciprocal thalamocortical pathway that produces electroencephalographic(EEG) sensorimotor rhythms (SMRs), and other CNS pathways.
 5. The methodaccording to claim 1, wherein the one or more other CNS pathway isselected from the group consisting of other spinal reflex pathways,other corticospinal connections, intracerebral connections, andcortical-subcortical pathways.
 6. The method according to claim 1,wherein the restored or improved nervous system function is selectedfrom the group consisting of locomotion (walking), a withdrawalresponse, hand control, arm control, reach-and-grasp control, attention,perception, emotional control, reading, arithmetic, memory, and othercognitive functions.
 7. A device for restoring or improving nervoussystem function of a subject, said device comprising: a nervestimulation-electromyographic recording component comprising a nervestimulator for stimulating a primary targeted central nervous system(CNS) pathway in a subject, at least one stimulating electrode array infunctional communication with the nerve stimulator and adapted fortopical contact with the subject, and at least one electromyographic(EMG) recording electrode array for recording EMG data of the subjectproduced in response to the stimulation of the primary targeted CNSpathway; and a controller for operating the nervestimulation-electromyographic recording component in accordance with anoperant conditioning protocol, wherein said operant conditioningprotocol is effective to produce targeted neural plasticity (TNP) in theprimary targeted CNS pathway of the subject.
 8. The device according toclaim 7, wherein the nerve stimulator comprises an apparatus forproviding a current or voltage pulse of selectable polarity, duration,and strength at externally triggered times through a pair ofskin-mounted electrodes selected from a stimulating electrode array. 9.The device according to claim 7, wherein the at least one stimulatingelectrode array comprises one or more possible pairs of stimulatingelectrodes.
 10. The device according to claim 7, wherein the at leastone EMG recording electrode array comprises one or more possible pairsof EMG recording electrode arrays.
 11. The device according to claim 7,wherein the operant conditioning protocol is effective to also elicitgeneralized neural plasticity (GNP) in one or more other CNS pathway,and wherein the elicitation of the GNP in the one or more other CNSpathway serves to restore or improve a nervous system function of thesubject.
 12. The device according to claim 7, wherein the controllercomprises a computer processor and corresponding software effective toperform the operant conditioning protocol on the subject.
 13. The deviceaccording to claim 12, wherein the software evaluates all possible pairsof stimulating electrodes to choose the most effective pair.
 14. Thedevice according to claim 12, wherein the software evaluates allpossible pairs of soleus muscle recording electrodes to choose the mosteffective pair.
 15. The device according to claim 12, wherein thesoftware automatically adjusts stimulus strength as needed to maintainthe target M wave.
 16. The device according to claim 12, wherein thesoftware automatically adjusts the amplitude criterion for reward asneeded to maintain an appropriate reward frequency.
 17. The deviceaccording to claim 12, wherein the software notifies the subject of anyproblem in EMG recording, in the responses obtained, or in other aspectsof operation, and provides instructions and oversight for resolving theproblem.
 18. The device according to claim 7, wherein the controllercomprises a monitoring component effective to provide real-time feedbackto the subject during performance of the operant conditioning protocol.19. The device according to claim 18, wherein the monitoring componentis effective to provide visual real-time feedback, audio real-timefeedback, both visual and audio real-time feedback, and/or other sensoryreal-time feedback to the subject.
 20. The device according to claim 7,wherein the controller is in communication with the nervestimulation-electromyographic recording component.
 21. The deviceaccording to claim 7, wherein the controller provides the subject withcomplete and appropriately illustrated instructions for donning anddoffing the device, parameterizing the operant conditioning protocol,performing the operant conditioning protocol, and handling associateddetails selected from the group consisting of data storage andInternet-based interaction with a therapist.
 22. The device according toclaim 7 further comprising: a wearable placement component forpositioning the at least one stimulating electrode array at astimulation target area of the subject and/or for positioning the atleast one EMG recording electrode array at an EMG recording target areaof the subject.
 23. The device according to claim 22, wherein thestimulation target area of the subject is an area of the skin of thesubject suitable for stimulating the primary targeted CNS pathway in thesubject.
 24. The device according to claim 22, wherein the EMG recordingtarget area of the subject is an area of the skin of the subjectsuitable for facilitating the recording of the recording EMG data of thesubject produced in response to the stimulation of the primary targetedCNS pathway.
 25. The device according to claim 7 further comprising: awireless communication device for receiving, displaying, storing, and/oranalyzing data generated by the controller.
 26. The device according toclaim 25, wherein the wireless communication device is selected from thegroup consisting of a computer, a computer tablet, a personal digitalassistant (PDA), a mobile phone, a portable digital media player, apersonal eyewear apparatus for receiving and displaying data generatedby the controller, and a dedicated digital device for receiving anddisplaying the data generated by the controller.
 27. A system forrestoring or improving nervous system function of a subject, said systemcomprising the device according to claim 7.